Combinations comprising substituted imidazo[1,5-α]pyrazinones as PDE1 inhibitors

ABSTRACT

The present invention provides combination treatments comprising compounds of Formula (I): 
                         
that are PDE1 enzyme inhibitors and other compounds useful in the treatment of psychiatric and/or cognitive disorders such as for example Attention Deficit Hyperactivity Disorder (ADHD), depression, anxiety, narcolepsy, schizophrenia, cognitive impairment or cognitive impairment associated with schizophrenia (CIAS). Separate aspects of the invention are directed to the combined use of said compounds for the treatment of psychiatric and/or cognitive disorders. The present invention also provides pharmaceutical compositions comprising said PDE1 enzyme inhibitors together with other compounds useful in the treatment of psychiatric and/or cognitive disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a National Stage filing under 35 U.S.C. 371 ofInternational Patent Application No. PCT/EP2017/077497, filed Oct. 26,2017, which claims foreign priority benefits are claimed under 35 U.S.C.§ 119(a)-(d) or 35 U.S.C. § 365(b) of Danish application NumberPA201600659, filed Oct. 28, 2016. The entire contents of theseapplications are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention provides combination treatments comprisingadministration of compounds that are PDE1 enzyme inhibitors and othercompounds useful in the treatment of psychiatric and/or cognitivedisorders such as for example Attention Deficit Hyperactivity Disorder(ADHD), depression, anxiety, narcolepsy, schizophrenia, cognitiveimpairment or cognitive impairment associated with schizophrenia (CIAS).Separate aspects of the invention are directed to the combined use ofsaid compounds for the treatment of psychiatric and/or cognitivedisorders. The present invention also provides pharmaceuticalcompositions comprising said PDE1 enzyme inhibitors together with othercompounds useful in the treatment of psychiatric and/or cognitivedisorders.

BACKGROUND OF THE INVENTION

Throughout this application, various publications are referenced infull. The disclosures of these publications are hereby incorporated byreference into this application to describe more fully the state of theart to which this invention pertains.

The second messenger cyclic Nucleotides (cNs), cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) play amajor role in intracellular signal transduction cascade, by regulatingcN-dependent protein kinases (PKA and PKG), EPACs (Exchange ProteinActivated by cAMP), phosphoprotein phosphatases, and/or cN-gated cationchannels. In neurons, this includes the activation of cAMP- andcGMP-dependent kinases and subsequent phosphorylation of proteinsinvolved in acute regulation of synaptic transmission as well as inneuronal differentiation and survival. Intracellular concentrations ofcAMP and cGMP are strictly regulated by the rate of biosynthesis bycyclases and by the rate of degradation by phosphodiesterases (PDEs, EC3.1.4.17). PDEs are bimetallic hydrolases that inactivate cAMP/cGMP bycatalytic hydrolysis of the 3′-ester bond, forming the inactive5′-monophosphate. Since PDEs provide the only means of degrading thecyclic nucleotides cAMP and cGMP in cells, PDEs play an essential rolein cyclic nucleotide signalling. The catalytic activities of PDEsprovide for breakdown of cNs over a spectrum of cN-concentrations in allcells, and their varied regulatory mechanisms provide for integrationand crosstalk with myriads of signalling pathways. Particular PDEs aretargeted to discrete compartments within cells where they control cNlevel and sculpt microenvironments for a variety of cN signalosomes(Sharron H. Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev2011, 91: 651-690).

On the basis of substrate specificity, the PDE families can be dividedinto three groups: 1) The cAMP-specific PDEs, which include PDE4, PDE7,and PDE8, 2) the cGMP-selective enzymes PDE5 and PDE9, and 3) thedual-substrate PDEs, PDE1, PDE2, PDE3, as well as PDE10 and PDE11.

Previously named calmodulin-stimulated PDE (CaM-PDE), PDE1 is unique inthat it is Ca²⁺-dependently regulated via calmodulin (CaM, a 16 kDaCa²⁺-binding protein) complexed with four Ca²⁺ (for review, Sharron H.Francis, Mitsi A. Blount, and Jackie D. Corbin. Physiol Rev 2011, 91:651-690). Thus, PDE1 represents an interesting regulatory link betweencyclic nucleotides and intracellular Ca²⁺. The PDE1 family is encoded bythree genes: PDE1A (mapped on human chromosome 2q32), PDE1B (humanchromosome location, hcl: 12q13) and PDE1C (hcl: 7p14.3). They havealternative promoters and give rise to a multitude of proteins byalternative splicing which differ in their regulatory properties,substrate affinities, specific activities, activation constants for CaM,tissue distribution and molecular weights. More than 10 human isoformsare identified. Their molecular weights vary from 58 to 86 kDa permonomer. The N-terminal regulatory domain that contains two Ca²⁺/CaMbinding domains and two phosphorylation sites differentiate theircorresponding proteins and modulate their biochemical functions. PDE1 isa dual substrate PDE and the PDE1C-subtype has equal activity towardscAMP and cGMP (Km≈1-3 μM), whereas the subtypes PDE1A and PDE1B have apreference for cGMP (Km for cGMP≈1-3 μM and for cAMP≈10-30 μM).

The PDE1 subtypes are highly enriched in the brain and locatedespecially in the striatum (PDE1B), hippocampus (PDE1A) and cortex(PDE1A) and this localization is conserved across species (Amy Bernardet al. Neuron 2012, 73, 1083-1099). In the cortex, PDE1A is presentmainly in deep cortical layers 5 and 6 (output layers), and used as aspecificity marker for the deep cortical layers. PDE1 inhibitors enhancethe levels of the second messenger cNs leading to enhanced neuronalexcitability.

Thus, PDE1 is a therapeutic target for regulation of intracellularsignaling pathways, preferably in the nervous system and PDE1 inhibitorscan enhance the levels of the second messengers cAMP/cGMP leading tomodulation of neuronal processes and to the expression of neuronalplasticity-related genes, neurotrophic factors, and neuroprotectivemolecules. These neuronal plasticity enhancement properties togetherwith the modulation of synaptic transmission make PDE1 inhibitors goodcandidates as therapeutic agents in many neurological and psychiatricconditions. The evaluation of PDE1 inhibitors in animal models (forreviews see e.g. Blokland et al. Expert Opinion on Therapeutic Patents(2012), 22(4), 349-354; and Medina, A. E. Frontiers in Neuropharmacology(2011), 5(February), 21) has suggested the potential for the therapeuticuse of PDE1 inhibitors in neurological disorders, like e.g. Alzheimer's,Parkinson's and Huntington's Diseases and in psychiatric disorders likee.g. Attention Deficit Hyperactivity Disorder (ADHD), restless legsyndrome, depression, anxiety, narcolepsy, schizophrenia, cognitiveimpairment and cognitive impairment associated with schizophrenia(CIAS).

WO 2013/053690 A1 discloses imidazopyrazinones that are inhibitors ofthe PDE9 enzyme.

WO 2016/055618 and WO 2016/147659 disclose triazolopyrazinones andimidazotriazinones as PDE1 inhibitors.

PDE1 inhibitors offer alternatives to current marketed treatments forpsychiatric and/or cognitive disorders, treatments which are notefficacious in all patients. Furthermore, it may be beneficial tocombine such PDE1 inhibitors with another treatment paradigm useful inthe treatment of psychiatric and/or cognitive disorders. There remains aneed for new methods of treatment of such diseases.

SUMMARY OF THE INVENTION

PDE1 enzymes are expressed in the Central Nervous System (CNS), makingthis gene family an attractive source of new targets for the treatmentof psychiatric and/or cognitive disorders.

The inventors of the present invention have provided compounds that arePDE1 inhibitors, and as such are useful to treat psychiatric and/orcognitive disorders. The combination of said new PDE1 inhibitors withother compounds that are useful in the treatment of a psychiatricdisorder may result in improved treatment of patients with psychiatricand/or cognitive disorders such as for example Attention DeficitHyperactivity Disorder (ADHD), depression, anxiety, narcolepsy,schizophrenia, cognitive impairment and cognitive impairment associatedwith schizophrenia (CIAS). Particular mention is made of cognitiveimpairment or cognitive impairment associated with schizophrenia (CIAS).

Preferrably, said PDE1 inhibitors are at least a ten-fold stronger asPDE1 inhibitors than as PDE9 inhibitors in order to prevent potentiallyunwanted effects associated with PDE9 inhibition.

Accordingly, the present invention relates to:

1) a compound of Formula (I)

whereinn is 0 or 1;q is 0 or 1;R1 is selected from the group consisting of benzyl, indanyl, indolineand 5-membered heteroaryls; all of which can be substituted with asubstituent selected from the group consisting of halogen and C₁-C₃alkyl; orR1 is selected from the group consisting of saturated monocyclic ringscontaining 4-6 carbon atoms and 1-2 nitrogen atoms; all of which can besubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine and sulfonamide; orR1 is selected from the group consisting of lactams containing 4-6carbon atoms; all of which can be substituted one or more times with oneor more substituents selected from the group consisting of methyl andfluorine; orR1 is selected from the group consisting of bicyclic ethers such as,7-oxabicyclo[2.2.1]heptane; all of which can be substituted one or moretimes with one or more substituents selected from the group consistingof methyl and fluorine; orR1 is selected from the group consisting of linear or branched C₁-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl and tetrahydropyranyl; all of which can be substitutedone or more times with one or more substituents selected from the groupconsisting of methyl, fluorine, hydroxy, cyano or methoxy; orR1 is a linear or branched C₁-C₃ alkyl, which is substituted with asubstituent selected from phenyl and 5-membered heteroaryl, wherein said5-membered heteroaryl can be substituted with one or more C₁-C₃ alkyls;orR1 is selected from the group consisting of morpholine,tetrahydrofuran-3-amine, hexahydro-2H-furo[3,2-b]pyrrole andhomomorpholine; all of which can be substituted with one or moresubstituents selected from the group consisting of C₁-C₃ alkyl;R2 is selected from the group consisting of hydrogen, linear or branchedC₁-C₈ alkyl, phenyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,benzo[d][1,3]dioxolyl, tetrahydrofuranyl and tetrahydropyranyl; orR2 is phenyl or pyridyl substituted with one or more substituentsselected from the group consisting of hydroxyl, amino, cyano, halogen,C₁-C₃ alkyl, C₁-C₃ alkoxy, C₃-C₅ cycloalkoxy, C₃-C₅ cycloalkyl-methoxy,C₁-C₃ fluoroalkoxy, and —NC(O)CH₃; orR2 is a 5-membered heteroaryl which can be substituted one or more timeswith C₁-C₃ alkyl;R3 is selected from the group consisting of hydrogen, halogen, C₁-C₅alkyl, C₃-C₅ cycloalkyl and phenyl; orR3 is selected from the group consisting of phenyl substituted one ormore times with C₁-C₃ alkyl; methyl substituted one, two or three timeswith fluorine; ethyl substituted one, two or three times with fluorine;R4 is hydrogen;and tautomers and pharmaceutically acceptable addition salts thereof;with the proviso that R2 and R3 cannot be hydrogen at the same time; and2) a second compound, which compound is useful in the treatment of apsychiatric disorder;wherein 1) and 2) are for combined use in the treatment of a psychiatricand/or cognitive disorder.

Reference to Compound (I) includes the free base of Compound (I),pharmaceutically acceptable salts of Compound (I), such as acid additionsalts of Compound (I), racemic mixtures of Compound (I), or thecorresponding enantiomer and/or optical isomer of Compound (I), andpolymorphic and amorphic forms of Compound (I) as well as tautomericforms of Compound (I). Furthermore, the compounds of this invention mayexist in unsolvated as well as in solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol and the like. In general, thesolvated forms are considered equivalent to the unsolvated forms for thepurposes of this invention.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising

1) a compound according formula (I); and

2) a second compound, which compound is useful in the treatment of apsychiatric disorder; and

one or more pharmaceutically acceptable carrier or excipient.

In one embodiment, the invention relates to a method for the treatmentof a psychiatric and/or cognitive disorder, which method comprises theadministration of:

1) a therapeutically effective amount of a compound according to Formula(I); and

2) a therapeutically effective amount of:

a second compound, which compound is useful in the treatment of apsychiatric disorder, to a patient in need thereof.

In one embodiment, the invention relates to the use of a compound ofFormula (I) in the manufacture of a medicament for use in the treatmentof a psychiatric and/or cognitive disorder; wherein said medicament isfor use in combination with a second compound, which compound is usefulin the treatment of a psychiatric disorder.

In one embodiment, the invention relates to the use of:

1) a compound of Formula (I); and

2) a second compound, which compound is useful in the treatment of apsychiatric disorder; in the manufacture of a medicament for use in thetreatment of a psychiatric and/or cognitive disorder.

DETAILED DESCRIPTION OF THE INVENTION Embodiments of the Invention

The following notation is applied: an embodiment of the invention isidentified as Ei, where i is an integer indicating the number of theembodiment. An embodiment Ei′ specifying a specific embodiment apreviously listed embodiment Ei is identified as Ei′(Ei), e.g. E2(E1)means “in an embodiment E2 of embodiment E1”.

Where an embodiment is a combination of two embodiments the notation issimilarly Ei″(Ei and Ei′), e.g. E3(E1 and E2) means “in an embodiment E3according to any of embodiments E2 and E1”

Where an embodiment is a combination of more than two embodiments thenotation is similarly Ei″′(Ei, Ei′ and Ei″) or (Ei-Ei″), e.g. E4(E1, E2and E3) or E4(E1-E3), means “in an embodiment E4 according to any ofembodiments E1, E2 and E3”

In a first embodiment E1, the present invention relates to:

1) A compound of Formula (I)

whereinn is 0 or 1;q is 0 or 1;R1 is selected from the group consisting of benzyl, indanyl, indolineand 5-membered heteroaryls; all of which can be substituted with asubstituent selected from the group consisting of halogen and C₁-C₃alkyl; orR1 is selected from the group consisting of saturated monocyclic ringscontaining 4-6 carbon atoms and 1-2 nitrogen atoms; all of which can besubstituted one or more times with one or more substituents selectedfrom the group consisting of methyl, fluorine and sulfonamide; orR1 is selected from the group consisting of lactams containing 4-6carbon atoms; all of which can be substituted one or more times with oneor more substituents selected from the group consisting of methyl andfluorine; orR1 is selected from the group consisting of bicyclic ethers such as,7-oxabicyclo[2.2.1]heptane; all of which can be substituted one or moretimes with one or more substituents selected from the group consistingof methyl and fluorine; orR1 is selected from the group consisting of linear or branched C₁-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl and tetrahydropyranyl; all of which can be substitutedone or more times with one or more substituents selected from the groupconsisting of methyl, fluorine, hydroxy, cyano or methoxy; orR1 is a linear or branched C₁-C₃ alkyl, which is substituted with asubstituent selected from phenyl and 5-membered heteroaryl, wherein said5-membered heteroaryl can be substituted with one or more C₁-C₃ alkyls;orR1 is selected from the group consisting of morpholine,tetrahydrofuran-3-amine, hexahydro-2H-furo[3,2-b]pyrrole andhomomorpholine; all of which can be substituted with one or moresubstituents selected from the group consisting of C₁-C₃ alkyl;R2 is selected from the group consisting of hydrogen, linear or branchedC₁-C₈ alkyl, phenyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,benzo[d][1,3]dioxolyl, tetrahydrofuranyl and tetrahydropyranyl; orR2 is phenyl or pyridyl substituted with one or more substituentsselected from the group consisting of hydroxyl, amino, cyano, halogen,C₁-C₃ alkyl, C₁-C₃ alkoxy, C₃-C₅ cycloalkoxy, C₃-C₅ cycloalkyl-methoxy,C₁-C₃ fluoroalkoxy, and —NC(O)CH₃; orR2 is a 5-membered heteroaryl which can be substituted with one or moreC₁-C₃ alkyl;R3 is selected from the group consisting of hydrogen, halogen, C₁-C₅alkyl, C₃-C₅ cycloalkyl and phenyl; orR3 is selected from the group consisting of phenyl substituted one ormore times with C₁-C₃ alkyl; methyl substituted one, two or three timeswith fluorine; ethyl substituted one, two or three times with fluorine;R4 is hydrogen;and tautomers and pharmaceutically acceptable addition salts thereof;with the proviso that R2 and R3 cannot be hydrogen at the same time; and2) a second compound, which compound is useful in the treatment of apsychiatric disorder; wherein 1) and 2) are for combined use in thetreatment of a psychiatric and/or cognitive disorder.

E2(E1) wherein said psychiatric and/or cognitive disorder is selectedfrom the group consisting of Attention Deficit Hyperactivity Disorder(ADHD), depression, anxiety, narcolepsy, schizophrenia, cognitiveimpairment and cognitive impairment associated with schizophrenia(CIAS).

E3(E1 and E2)

n is 0 or 1;

q is 0 or 1;

R1 is selected from the group consisting of linear or branched C₁-C₈alkyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl, and tetrahydropyranyl;

R2 is selected from the group consisting of, linear or branched C₁-C₈alkyl, phenyl, and saturated monocyclic C₃-C₈ cycloalkyl; or

R2 is selected from the group consisting of phenyl substituted with oneor more times with one or more substituents selected from the groupconsisting of halogen, C₁-C₃ alkyl and methoxy;

R3 is selected from the group consisting of hydrogen, C₁-C₃ alkyl andhalogen;

R4 is hydrogen.

E4(E1 to E3) R1 is tetrahydropyranyl.

E5(E1 to E3) R1 is C₁-C₃ alkyl or C₃-C₅ cycloalkyl.

E6(E1 and E5) R1 is propyl or cyclopropyl

E7(E1 to E6) R2 is phenyl.

E8(E1 to E6) R2 is substituted phenyl, wherein the one or moresubstituents are selected from the group consisting of fluorine,chlorine, methyl and methoxy.

E9(E1 to E6) R2 is saturated monocyclic C₃-C₈ cycloalkyl.

E10(E1 and E9) R2 is saturated monocyclic C₅-C₇ cycloalkyl.

E11(E1 to E6) R2 is C₁-C₃ alkyl.

E12(E1 and E11) R2 is methyl, ethyl or isopropyl

E13(E1 to E12) R3 is bromine

E14(E1 to E12) R3 is methyl

E15(E1 to E2) R3 is selected from hydrogen and methyl; and

R2 is selected from the group consisting of linear or branched C₁-C₈alkyl, phenyl, saturated monocyclic C₃-C₈ cycloalkyl, oxetanyl,tetrahydrofuranyl and tetrahydropyranyl; or

R2 is phenyl or pyridyl substituted with one or more substituentsselected from the group consisting of hydroxyl, amino, cyano, halogen,C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ fluoroalkoxy, and —NC(O)CH₃; or

R2 is a 5-membered heteroaryl which can be substituted with C₁-C₃ alkyl.

E16(E1 to E15) n is 0.

E17(E1 to E15) n is 1.

E18(E1 to E16) q is 0.

E19(E1 to E16) q is 1.

E20(E1) the compound of Formula (I) is selected among the compoundslisted in Table 1, in the form of the free base, one or more tautomersthereof or a pharmaceutically acceptable salt thereof.

E21(E1 to E20) the compound of Formula (I) has a PDE1A, PDE1B or PDE1CIC₅₀ value, determined as described in the section “PDE1 inhibitionassay”, of 10 micro molar or less, such as 5 micro molar or less, suchas 4 micro molar or less, such as 3 micro molar or less, such as 2 micromolar or less, such as 1 micro molar or less, such as 500 nM or less,such as 400 nM or less, such as 300 nM or less, such as 200 nM or less,such as 100 nM or less.

E22(E1) the compound or Formula (I) is selected from the compoundslisted in Table 1 and pharmaceutically acceptable salts thereof.

E23(E1 to E22) the compound of Formula (I) is at least 10 times strongerPDE1 inhibitors than PDE9 inhibitors, such as at least 50 times strongerPDE1 inhibitors than PDE9 inhibitors or even at least 100 times strongerPDE1 inhibitors than PDE9 inhibitors.

E24 A pharmaceutical composition comprising:

1) a compound of Formula (I) as described according to any ofembodiments (E1) to (E23); and

2) a second compound, which compound is useful in the treatment of apsychiatric disorder; and

one or more pharmaceutically acceptable carriers, diluents andexcipients.

E25(E24) the pharmaceutical composition is for the treatment of apsychiatric and/or cognitive disorder.

E26 A method for the treatment of a subject suffering from a psychiatricand/or cognitive disorder, which method comprises administering to saidsubject:

1) a therapeutically effective amount of a compound of Formula (I) asdescribed according to any of embodiments (E1) to E23); and

2) a therapeutically effective amount of:

a second compound, which compound is useful in the treatment of apsychiatric disorder.

E27 A combination of:

1) a compound of Formula (I) as described according to any ofembodiments (E1) to E23); and

2) a second compound, which compound is useful in the treatment of apsychiatric disorder; wherein said combination is for use in thetreatment of a psychiatric and/or cognitive disorder.

E28 Use of:

1) a compound of Formula (I) as described according to any ofembodiments (E1) to (E23); and

2) a second compound, which compound is useful in the treatment of apsychiatric disorder; in the manufacture of a medicament for use in thetreatment of a psychiatric and/or cognitive disorder.

E29 Use of a compound of Formula (I) in the manufacture of a medicamentfor use in the treatment of a psychiatric and/or cognitive disorder;wherein said medicament is for use in combination with a secondcompound, which compound is useful in the treatment of a psychiatricdisorder.

E30 A kit comprising:

1) a compound of Formula (I) as described according to any ofembodiments (E1) to (E23); and

2) a second compound, which compound is useful in the treatment of apsychiatric disorder.

E31(E30) the kit comprises the compound of formula (I) and the compoundlisted under item 2) in E1,

in therapeutically effective amounts.

E32(E30 and E31) the kit is for the treatment of a psychiatric and/orcognitive disorder.

E33(E25 to E29 and E31) said psychiatric and/or cognitive disorder isselected from the group consisting of Attention Deficit HyperactivityDisorder (ADHD), depression, anxiety, narcolepsy, schizophrenia,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS).

E34(E2 and E33) said psychiatric and/or cognitive disorder is cognitiveimpairment associated with schizophrenia (CIAS).

E35(E1 to E34) said second compound, which compound is useful in thetreatment of a psychiatric disorder is an antipsychotic agent.

E36(E1 to E35) said second compound, which compound is useful in thetreatment of a psychiatric disorder has a pharmacological activityselected from one or more of the following mechanisms:antagonist/inverse agonist/negative modulator/partial agonist/inhibitorof one or more of the targets dopamine D1 receptor, dopamine D2receptor, dopamine D3 receptor, phosphodiesterase PDE10, serotonin5-HT2A receptor, serotonin 5-HT6 receptor, and glycine transporterGlyT1; or agonist/positive modulator/partial agonist of one or more ofthe targets KCNQ channel, NMDA receptor, AMPA receptor and nicotinicalpha-7 receptor.

E37(E1 to E35) said second compound, which compound is useful in thetreatment of a psychiatric disorder is selected from the list comprisingclozapine, risperidone, paliperidone, olanzapine, quetiapine,amisulpride, ziprasidone, aripiprazole, brexpiprazole, asenapine,haloperidole, iloperidone, lurasidone, chlorpromazine, blonanserin,perphenazine, levomepromazine, sulpiride, fluphenazine, zuclopenthixol,flupenthixol and cariprazine.

Definitions

PDE1 Enzymes

The PDE1 isozyme family includes numerous splice variant PDE1 isoforms.It has three subtypes, PDE1A, PDE1B and PDE1C which divide further intovarious isoforms. In the context of the present invention PDE1 and PDE1enzymes are synonymous and refer to PDE1A, PDE1B and PDE1C enzymes aswell as their isoforms unless otherwise specified.

Substituents

As used in the context of the present invention, the terms “halo” and“halogen” are used interchangeably and refer to fluorine, chlorine,bromine or iodine.

A given range may interchangeably be indicated with “-” (dash) or “to”,e.g. the term “C₁-C₃ alkyl” is equivalent to “C₁ to C₃ alkyl”.

The terms “C₁-C₃ alkyl”, “C₁-C₄ alkyl”, “C₁-C₅ alkyl”, “C₀-C₆ alkyl”,“C₁-C₇ alkyl” and “C₁-C₈ alkyl” refer to a linear (i.e. unbranched) orbranched saturated hydrocarbon having from one up to eight carbon atoms,inclusive. Examples of such groups include, but are not limited to,methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl,2-methyl-1-butyl, n-hexyl, n-heptyl and n-octyl.

The term saturated monocyclic C₃-C₈ cycloalkyl refers to cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Theterm C₃-C₅ cycloalkyl refers to cyclopropyl, cyclobutyl and cyclopentyl.

The term “C₁-C₃ alkoxy” refers to a moiety of the formula —OR′, whereinR′ indicates C₁-C₃ alkyl as defined above. The term “C₃-C₅ cycloalkoxy”refers to a moiety of the formula —OR′, wherein R′ indicates C₃-C₅cycloalkyl as defined above. The term “C₃-C₅ cycloalkyl-methoxy” refersto a moiety of the formula —OCH₂R′, wherein R′ indicates C₃-C₅cycloalkyl as defined above. C₁-C₃ fluoroalkoxy refers to a C₁-C₃ alkoxysubstituted with one or more fluorine. 5-membered heteroaryls aredefined as 5 membered aromatic rings containing at least one atomselected from nitrogen, sulfur and oxygen. Examples include, but are notlimited to thiazole, thiophene and isoxazole.

The term “lactams containing 4-6 carbon atoms” refers topyrrolidin-2-one, piperidin-2-one or azepan-2-one

Isomeric Forms

Where compounds of Formula (I) contain one or more chiral centersreference to any of the compounds will, unless otherwise specified,cover the enantiomerically or diastereomerically pure compound as wellas mixtures of the enantiomers or diastereomers in any ratio.

The above also applies where compounds of Formula (I) contain more thantwo chiral centers.

PDE1 Inhibitors and PDE9 Inhibitors

In the context of the present invention a compound of Formula (I) isconsidered to be a PDE1 inhibitor if the amount required to reach theIC₅₀ level of one or more of the three PDE1 isoforms is 10 micro molaror less, preferably less than 9 micro molar, such as 8 micro molar orless, such as 7 micro molar or less, such as 6 micro molar or less, suchas 5 micro molar or less, such as 4 micro molar or less, such as 3 micromolar or less, more preferably 2 micro molar or less, such as 1 micromolar or less, in particular 500 nM or less. In preferred embodiment therequired amount of PDE1 inhibitor required to reach the IC₅₀ level ofPDE1B is 400 nM or less, such as 300 nM or less, 200 nM or less, 100 nMor less, or even 80 nM or less, such as 50 nM or less, for example 25 nMor less.

In a preferred embodiment, the compounds of Formula (I) are at least aten-fold stronger as PDE1 inhibitors than as PDE9 inhibitors, i.e. theamount of the compound required to reach the IC₅₀ level of one or moreof the three PDE1 isoforms is at least a ten-fold less than the amountof the same compound required to reach the IC₅₀ level of the PDE9enzyme.

Pharmaceutically Acceptable Salts

The combinations of the present invention also comprise salts of thecompounds of Formula (I), typically, pharmaceutically acceptable salts.Such salts include pharmaceutically acceptable acid addition salts. Acidaddition salts include salts of inorganic acids as well as organicacids.

Representative examples of suitable inorganic acids includehydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic,lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic,picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic,tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids,theophylline acetic acids, as well as the 8-halotheophyllines, forexample 8-bromotheophylline and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Berge, S. M. etal., J. Pharm. Sci. 1977, 66, 2, the contents of which are herebyincorporated by reference.

Furthermore, the compounds of Formula (I) may exist in unsolvated aswell as in solvated forms with pharmaceutically acceptable solvents suchas water, ethanol and the like. In general, the solvated forms areconsidered equivalent to the unsolvated forms for the purposes of thisinvention.

Therapeutically Effective Amount

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to cure, alleviate or partiallyarrest the clinical manifestations of a given disease and itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

The methods of the present invention provide for administration ofcombinations of compounds. In such instances an “effective amount”indicates an amount of each individual compound that, when saidcompounds are given in combination, is sufficient to cause the intendedpharmacological effect. A therapeutically effective amount of a compoundwhen administered in combination with another compound may in someinstances be lower than a therapeutically effective amount of saidcompound when administered on its own.

Treatment and Treating

In the present context, the term “treatment” and “treating” means themanagement and care of a patient for the purpose of combating acondition, such as a disease or a disorder. The term is intended toinclude the full spectrum of treatments for a given condition from whichthe patient is suffering, such as administration of the active compoundto alleviate the symptoms or complications, to delay the progression ofthe disease, disorder or condition, to alleviate or relief the symptomsand complications, and/or to cure or eliminate the disease, disorder orcondition.

In an embodiment, “treatment” and “treating” also relates to preventionof the condition, wherein prevention is to be understood as themanagement and care of a patient for the purpose of combating thedisease, condition, or disorder and includes the administration of theactive compounds to prevent the onset of the symptoms or complications.Nonetheless, prophylactic (preventive) and therapeutic treatments aretwo separate aspects of the invention.

The patient to be treated is preferably a mammal, in particular a humanbeing.

Pharmaceutical Compositions

The present invention further provides a pharmaceutical compositioncomprising 1) a compound of Formula (I), such as one of the specificcompounds disclosed in the Experimental section herein; and 2) a secondcompound, which compound is useful in the treatment of a psychiatricdisorder; and a pharmaceutically acceptable carrier or diluent.

The present invention also provides 1) a pharmaceutical compositioncomprising a compound of Formula (I), such as one of the specificcompounds disclosed in the Experimental Section herein, and apharmaceutically acceptable carrier or diluent; and 2) a pharmaceuticalcomposition comprising a second compound, which compound is useful inthe treatment of a psychiatric disorder, and a pharmaceuticallyacceptable carrier or diluent; wherein said pharmaceutical compositionsare for combined use in the treatment of a psychiatric and/or cognitivedisorder.

The compounds of Formula (I) and/or the compounds listed under item 2);and/or the combinations thereof may be administered in furthercombination with pharmaceutically acceptable carriers, diluents orexcipients, in either single or multiple doses. The pharmaceuticalcompositions according to the invention may be formulated withpharmaceutically acceptable carriers or diluents as well as any otherknown adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 21^(st) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 2005.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal andparenteral (including subcutaneous, intramuscular and intravenous)routes. It will be appreciated that the route will depend on the generalcondition and age of the subject to be treated, the nature of thecondition to be treated and the active ingredient.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, the compositions may be prepared withcoatings such as enteric coatings or they may be formulated so as toprovide controlled release of the active ingredient such as sustained orprolonged release according to methods well known in the art. Liquiddosage forms for oral administration include solutions, emulsions,suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Othersuitable administration forms include, but are not limited to,suppositories, sprays, ointments, creams, gels, inhalants, dermalpatches and implants.

Typical oral dosages range from about 0.001 to about 100 mg/kg bodyweight per day. Typical oral dosages also range from about 0.01 to about50 mg/kg body weight per day. Typical oral dosages further range fromabout 0.05 to about 10 mg/kg body weight per day. Oral dosages areusually administered in one or more dosages, typically, one to threedosages per day. The exact dosage will depend upon the frequency andmode of administration, the sex, age, weight and general condition ofthe subject treated, the nature and severity of the condition treatedand any concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may also be presented in a unit dosage form by methodsknown to those skilled in the art. For illustrative purposes, a typicalunit dosage form for oral administration may contain from about 0.01 toabout 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg toabout 200 mg.

The compounds of Formula (I) are generally utilized as the freesubstance or as a pharmaceutically acceptable salt thereof. One exampleis an acid addition salt of a compound which has the same utility as ofa free base. When a compound of Formula (I) contains a free base suchsalts are prepared in a conventional manner by treating a solution orsuspension of a free base of Formula (I) with a pharmaceuticallyacceptable acid. Representative examples of suitable organic andinorganic acids are described above.

For parenteral administration, solutions of the compounds of Formula (I)in sterile aqueous solution, aqueous propylene glycol or sesame orpeanut oil may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. The aqueous solutions areparticularly suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The compounds of Formula (I) may bereadily incorporated into known sterile aqueous media using standardtechniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions and various organic solvents.Examples of solid carriers include lactose, terra alba, sucrose,cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and lower alkyl ethers of cellulose. Examples of liquidcarriers include, but are not limited to, syrup, peanut oil, olive oil,phospholipids, fatty acids, fatty acid amines, polyoxyethylene andwater. Similarly, the carrier or diluent may include any sustainedrelease material known in the art, such as glyceryl monostearate orglyceryl distearate, alone or mixed with a wax. The pharmaceuticalcompositions formed by combining the compounds of Formula (I) and apharmaceutically acceptable carrier are then readily administered in avariety of dosage forms suitable for the disclosed routes ofadministration. The formulations may conveniently be presented in unitdosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, andoptionally a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation maybe tableted, placed in a hard gelatin capsule in powder or pellet formor it may be in the form of a troche or lozenge. The amount of solidcarrier will vary widely but will range from about 25 mg to about 1 gper dosage unit. If a liquid carrier is used, the preparation may be inthe form of a syrup, emulsion, soft gelatin capsule or sterileinjectable liquid such as an aqueous or non-aqueous liquid suspension orsolution.

The pharmaceutical compositions of the invention may be prepared byconventional methods in the art. For example, tablets may be prepared bymixing the active ingredient with ordinary adjuvants and/or diluents andsubsequently compressing the mixture in a conventional tableting machineprepare tablets. Examples of adjuvants or diluents comprise: cornstarch, potato starch, talcum, magnesium stearate, gelatin, lactose,gums, and the like. Any other adjuvants or additives usually used forsuch purposes such as colorings, flavorings, preservatives etc. may beused provided that they are compatible with the active ingredients.

Treatment of Disorders

As mentioned above, the compounds of Formula (I) are PDE1 enzymeinhibitors and as such are useful to treat associated psychiatric andcognitive disorders. It may be beneficial to combine such PDE1inhibitors with another treatment paradigm useful in the treatment ofpsychiatric and/or cognitive disorders. Hence, the invention relates tocombination treatments wherein compounds of Formula (I) are combinedwith another compound useful in the treatment of such disorders. Saidpsychiatric and/or cognitive disorder may for example be selected fromthe group consisting of Attention Deficit Hyperactivity Disorder (ADHD),depression, anxiety, narcolepsy, schizophrenia, cognitive impairment andcognitive impairment associated with schizophrenia (CIAS). In aparticular embodiment, said psychiatric and/or cognitive disorder iscognitive impairment associated with schizophrenia (CIAS).

The invention thus provides 1) a compound of Formula (I) or a tautomeror pharmaceutically acceptable acid addition salt thereof; and 2) asecond compound, which compound is useful in the treatment of apsychiatric disorder; for combined use in the treatment of a psychiatricand/or cognitive disorder such as Attention Deficit HyperactivityDisorder (ADHD), depression, anxiety, narcolepsy, schizophrenia,cognitive impairment and cognitive impairment associated withschizophrenia (CIAS).

Combinations

The terms “combined use”, “in combination with” and “a combination of”and the like as used herein in the context of the method of theinvention comprising the combined administration of therapeuticallyeffective amounts of 1) a PDE1 inhibitor of Formula (I), and 2) a secondcompound, which compound is useful in the treatment of a psychiatricdisorder; is intended to mean the administration of a PDE1 inhibitor ofFormula (I) simultaneously or sequentially, in any order, together witha compound listed under item 2).

The two compounds may be administered simultaneously or with a time gapbetween the administrations of the two compounds. The two compounds maybe administered either as part of the same pharmaceutical formulation orcomposition, or in separate pharmaceutical formulations or compositions.The two compounds may be administered on the same day or on differentdays. They may be administered by the same route, such as by oraladministration, or by depot, or by intramuscular or intraperitonealinjection, or by intravenous injection; or by different routes whereinone compound is for example administered orally or placed by depot andthe other compound is injected, or wherein one compound is for exampleplaced by depot and the other is administered orally or injected. Thetwo compounds may be administered by the same dosage regime or interval,such as once or twice daily, weekly, or monthly; or by different dosageregimes for example wherein one is administered once daily and the otheris administered twice daily, weekly or monthly.

In some instances, the patient to be treated may already be in treatmentwith one or more compounds listed under item 2) when treatment with acompound of Formula (I) is initiated. In other instances, the patientmay already be in treatment with a compound of Formula (I) whentreatment with one or more of the compounds listed under item 2) isinitiated. In other instances, the treatment with a compound of Formula(I) and treatment with a compound of listed under item 2) is initiatedat the same time.

Compounds for Combination Treatment

Antipsychotic agents are used to treat the symptoms of schizophrenia andbipolar disorder.

Current antipsychotics primarily reduce positive symptoms ofschizophrenia, while their effects on negative and cognitive symptomsare marginal. All current antipsychotics are either antagonists orpartial agonists at the dopamine D2 receptor at therapeutically relevantdoses and it is believed that this is central for their antipsychoticeffect (Seeman P; Can. J. Psychiatry; 2002; 47(1):27-38).

In addition to dopamine D2 receptors, most antipsychotics also haverelevant affinity for other receptors such as other dopamine receptors,serotonergic receptors and adrenergic receptors. Differentantipsychotics vary from one another in their affinity for thesereceptors, and these differences in receptor activity are hypothesizedto account for differences in efficacy, safety, and tolerability amongdifferent antipsychotics. Examples of antipsychotic agents and theirmechanisms of action are provided below.

The antipsychotic effect of risperidone, olanzapine, quetiapine, andziprasidone is proposed to be primarily via dopamine D2 and serotonin(5-HT2A) receptor antagonism. However, each drug has varying effects onthese and other receptors. Antagonism of the 5-HT2A receptors is thoughtto reduce the motor side effect associated with dopamine D2 receptorantagonism in the striatum while leaving the effect of blockade of D2receptors in the limbic area unaffected. Most so-called atypicalantipsychotics are potent antagonists of 5-HT2A and this may in partaccount for fewer extrapyramidal side effects and better effects on thenegative symptoms of schizophrenia compared with conventionalantipsychotics.

Clozapine stands out for having effect in some patients that areunresponsive to other antipsychotics. It also exhibits antipsychoticeffects at lower dopamine D2 receptor occupancy compared to most otherantipsychotic drugs. This may be related to its significant affinity forthe dopamine D1 receptor in addition to dopamine D2 receptors, but italso interacts with a number of other receptors that may contribute.

Aripiprazole and brexpiprazole have unique pharmacological propertiesrelative to the other atypical antipsychotics. They are partial agonistsat dopamine D2 receptors; thus, they are functional antagonists in thepresence of high levels of endogenous dopamine and, conversely, act asagonists when minimal dopamine is present.

In the present context, “a second compound, which compound is useful inthe treatment of a psychiatric disorder” is preferably an antipsychoticagent. The pharmacological mechanism for the action of said compound mayfor example be selected from one or more of the following mechanisms:antagonist/inverse agonist/negative modulator/partial agonist/inhibitorof one or more of the targets dopamine D1 receptor, dopamine D2receptor, dopamine D3 receptor, phosphodiesterase PDE10, serotonin5-HT2A receptor, serotonin 5-HT6 receptor, and glycine transporterGlyT1; or agonist/positive modulator/partial agonist of one or more ofthe targets KCNQ channel, NMDA receptor, AMPA receptor and nicotinicalpha-7 receptor. In an embodiment, said “second compound, whichcompound is useful in the treatment of a psychiatric disorder” is acompound which is an antagonist or partial agonist of the dopamine D2receptor. In an embodiment, said “second compound, which compound isuseful in the treatment of a psychiatric disorder” is a compound whichis an antagonist or partial agonist of the dopamine D2 receptor andoptionally also exhibits an activity selected from one or more of thefollowing mechanisms: antagonist/inverse agonist/negativemodulator/partial agonist/inhibitor of one or more of the targetsdopamine D1 receptor, dopamine D2 receptor, dopamine D3 receptor,phosphodiesterase PDE10, serotonin 5-HT2A receptor, serotonin 5-HT6receptor, and glycine transporter GlyT1; or agonist/positivemodulator/partial agonist of one or more of the targets KCNQ channel,NMDA receptor, AMPA receptor and nicotinic alpha-7 receptor.

Examples of “a second compound, which compound is useful in thetreatment of a psychiatric disorder” include, but are not limited toclozapine, risperidone, paliperidone, olanzapine, quetiapine,amisulpride, ziprasidone, aripiprazole, brexpiprazole, asenapine,haloperidole, iloperidone, lurasidone, chlorpromazine, blonanserin,perphenazine, levomepromazine, sulpiride, fluphenazine, zuclopenthixol,flupenthixol and cariprazine.

All references, including publications, patent applications and patents,cited herein are hereby incorporated by reference in their entirety andto the same extent as if each reference were individually andspecifically indicated to be incorporated by reference and were setforth in its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, andshould not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including “forinstance”, “for example”, “e.g.”, and “as such”) in the presentspecification is intended merely to better illuminate the invention, anddoes not pose a limitation on the scope of invention unless otherwiseindicated.

The citation and incorporation of patent documents herein is done forconvenience only, and does not reflect any view of the validity,patentability and/or enforceability of such patent documents.

The present invention includes all modifications and equivalents of thesubject-matter recited in the claims appended hereto, as permitted byapplicable law.

Compounds of Formula (I)

TABLE 1 Compounds of Formula (I) % inhibition PDE1A, PDE1B, PDE1C, ofPDE9 at Example Name IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 10 microM 17-(3-Fluorobenzyl)-3- 801 790 300 −12 propylimidazo[1,5-a]pyrazin-8(7H)-one 2 6-Benzyl-7-(3-fluorobenzyl)-3- 51 14 11 −14(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 36-Benzyl-7-(cyclohexylmethyl)-3- 8 12 6 −6 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 4 7-(Cyclohexylmethyl)-6-methyl-3-11 25 7 −5 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 57-(3-Fluorobenzyl)-6-methyl-3- 108 120 14 18 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 6 3-Cyclopropyl-7-(3- 68% 81% 290 25fluorobenzyl)imidazo[1,5- (at 2 μM) (at 2 μM) a]pyrazin-8(7H)-one 77-(Cyclopentylmethyl)-3- 60% 85% 230 1 cyclopropylimidazo[1,5-a]pyrazin-(at 2 μM) (at 2 μM) 8(7H)-one 8 7-(Cyclohexylmethyl)-3- 252 67 100 9cyclopropylimidazo[1,5-a]pyrazin- 8(7H)-one 97-(3-Fluorobenzyl)-3-(tetrahydro- 68% 90% 170 22H-pyran-4-yl)imidazo[1,5- (at 2 μM) (at 2 μM) a]pyrazin-8(7H)-one 107-(Cyclopentylmethyl)-3- 73% 88% 79 8 (tetrahydro-2H-pyran-4- (at 2 μM)(at 2 μM) yl)imidazo[1,5-a]pyrazin-8(7H)- one 11 7-(Cyclohexylmethyl)-3-113 72 43 18 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one12 7-(Cycloheptylmethyl)-3- 30 21 16 12 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 13 7-(Cycloheptylmethyl)-3- 87 50 627 cyclopropylimidazo[1,5-a]pyrazin- 8(7H)-one 147-(4-Chlorobenzyl)-6-methyl-3- 18 15 51 22 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 15 6-Bromo-7-(3-fluorobenzyl)-3- 58115 15 15 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 167-Benzyl-6-methyl-3-(tetrahydro- 85 57 12 19 2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 17 7-(2-Fluorobenzyl)-6-methyl-3- 42 36 9 7(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 187-(3-Chlorobenzyl)-6-methyl-3- 57 49 8 31 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 19 7-(2-Chlorobenzyl)-6-methyl-3- 4668 10 18 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 207-(3-Methoxybenzyl)-6-methyl-3- 416 175 62 −38 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 21 6-Methyl-7-(2-methylbenzyl)-3-242 195 30 −14 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)-one 22 6-Methyl-7-(4-methylbenzyl)-3- 75 28 67 50(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 237-(4-Methoxybenzyl)-6-methyl-3- 14 12 19 16 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 24 7-(4-Fluorobenzyl)-6-methyl-3- 3843 17 −1 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 256-Methyl-7-(3-methylbenzyl)-3- 63 57 9 −42 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 26 7-(3-fluorobenzyl)-6-methyl-3-(4-234 218 47 −2 methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 27 4-(7-(3-fluorobenzyl)-6-methyl-8-603 699 103 5 oxo-7,8-dihydroimidazo[1,5- a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile 28 7-(3-fluorobenzyl)-3-(4- 663 737 72 13methoxytetrahydro-2H-pyran-4- yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one 29 7-(3-fluorobenzyl)-3-(4- 493 249 50 16fluorotetrahydro-2H-pyran-4-yl)- 6-methylimidazo[1,5-a]pyrazin-8(7H)-one 30, isomer 7-(3-fluorobenzyl)-6-methyl-3- 20% 615 225 −11 1(tetrahydro-2H-pyran-2- (at 1 μM) yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 1 30, isomer 7-(3-fluorobenzyl)-6-methyl-3- 27% 40% 215 282 (tetrahydro-2H-pyran-2- (at 1 μM) (at 1 μM)yl)imidazo[1,5-a]pyrazin-8(7H)- one, stereoisomer 2 31, isomer7-(3-fluorobenzyl)-6-methyl-3- 337 106 27 −1 1(tetrahydrofuran-3-yl)imidazo[1,5- a]pyrazin-8(7H)-one, stereoisomer 131, isomer 7-(3-fluorobenzyl)-6-methyl-3- 347 138 31 5 2(tetrahydrofuran-3-yl)imidazo[1,5- a]pyrazin-8(7H)-one, stereoisomer 232, isomer 7-(3-fluorobenzyl)-6-methyl-3-(3- 257 122 22 −1 1methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 1 32, isomer 7-(3-fluorobenzyl)-6-methyl-3-(3- 401 170 4016 2 methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 2 33 7-(3-fluorobenzyl)-6-methyl-3-(1- 94 52 7 −2methylcyclopropyl)imidazo[1,5- a]pyrazin-8(7H)-one 343-(2,2-difluorocyclopropyl)-7-(3- 331 359 93 0 fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin- 8(7H)-one 35, isomer7-(3-fluorobenzyl)-6-methyl-3-(2- 193 75 19 −11 1methylcyclopropyl)imidazo[1,5- a]pyrazin-8(7H)-one, stereoisomer 1 35,isomer 7-(3-fluorobenzyl)-6-methyl-3-(2- 364 166 41 15 2methylcyclopropyl)imidazo[1,5- a]pyrazin-8(7H)-one, stereoisomer 2 35,isomer 7-(3-fluorobenzyl)-6-methyl-3-(2- 82 18 8 0 3methylcyclopropyl)imidazo[1,5- a]pyrazin-8(7H)-one, stereoisomer 3 35,isomer 7-(3-fluorobenzyl)-6-methyl-3-(2- 43% 360 85 5 4methylcyclopropyl)imidazo[1,5- (at 1 μM) a]pyrazin-8(7H)-one,stereoisomer 4 36, isomer 7-(3-fluorobenzyl)-6-methyl-3-(2- 152 59 15 31 methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 1 36, isomer 7-(3-fluorobenzyl)-6-methyl-3-(2- 282 107 3811 2 methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 2 36, isomer 7-(3-fluorobenzyl)-6-methyl-3-(2- 77 21 7 −103 methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 3 36, isomer 7-(3-fluorobenzyl)-6-methyl-3-(2- 51 520 40%11 4 methyltetrahydrofuran-3- (at 1 μM) yl)imidazo[1,5-a]pyrazin-8(7H)-one, stereoisomer 4 37, isomer 7-(3-fluorobenzyl)-3-(cis-2- 1140 1180345 −2 1 fluorocyclopropyl)-6- methylimidazo[1,5-a]pyrazin- 8(7H)-one,stereoisomer 1 37, isomer 7-(3-fluorobenzyl)-3-(cis-2- 149 164 55 13 2fluorocyclopropyl)-6- methylimidazo[1,5-a]pyrazin- 8(7H)-one,stereoisomer 2 38, isomer 7-(3-fluorobenzyl)-3-(trans-2- 582 601 118 −11 fluorocyclopropyl)-6- methylimidazo[1,5-a]pyrazin- 8(7H)-one,stereoisomer 1 38, isomer 7-(3-fluorobenzyl)-3-(trans-2- 667 667 153 2 2fluorocyclopropyl)-6- methylimidazo[1,5-a]pyrazin- 8(7H)-one,stereoisomer 2 39 7-(4-cyclopropoxybenzyl)-6- 413 118 364 23methyl-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 407-(4-(difluoromethoxy)benzyl)-6- 73 27 52 −25methyl-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 416-methyl-3-(tetrahydro-2H-pyran- 27 18 52 −22 4-yl)-7-(4-(trifluoromethoxy)benzyl)imidazo[1,5- a]pyrazin-8(7H)-one 42 7-(4- 50%155 55% 15 (cyclopropylmethoxy)benzyl)-6- (at 1 μM) (at 1 μM)methyl-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 437-benzyl-6-ethyl-3-(tetrahydro- 105 32 9 6 2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 44 6-ethyl-7-(4-methoxybenzyl)-3- 40 5 16 18(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 453-((6-methyl-8-oxo-3-(tetrahydro- 64 54% 149 62H-pyran-4-yl)imidazo[1,5- (at 2 μM) (at 1 μM) a]pyrazin-7(8H)-yl)methyl)benzonitrile 46 4-((6-methyl-8-oxo-3-(tetrahydro- 809 58%  9%14 2H-pyran-4-yl)imidazo[1,5- (at 1 μM) (at 1 μM) a]pyrazin-7(8H)-yl)methyl)benzonitrile 47 N-(4-((6-methyl-8-oxo-3-  0% 388 10% 10(tetrahydro-2H-pyran-4- (at 1 μM) (at 1 μM)yl)imidazo[1,5-a]pyrazin-7(8H)- yl)methyl)phenyl)acetamide 487-(4-chloro-3-methoxybenzyl)-6- — 54% 34% 10methyl-3-(tetrahydro-2H-pyran-4- (at 1 μM) (at 1 μM)yl)imidazo[1,5-a]pyrazin-8(7H)- one 49 7-(2-ethylbenzyl)-6-methyl-3- 4460% 173 1 (tetrahydro-2H-pyran-4- (at 2 μM) (at 1 μM)yl)imidazo[1,5-a]pyrazin-8(7H)- one 50 7-(benzo[d][1,3]dioxol-5- 50 1638 12 ylmethyl)-6-methyl-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 51 7-(3-chloro-4-methoxybenzyl)-6- 199 36 46 1methyl-3-(tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 527-(4-aminobenzyl)-6-methyl-3-  0% 388 10% −3 (tetrahydro-2H-pyran-4- (at1 μM) (at 1 μM) yl)imidazo[1,5-a]pyrazin-8(7H)- one 537-(4-hydroxybenzyl)-6-methyl-3- 401 35 84 −41 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 54 6-ethyl-7-(3-fluorobenzyl)-3- 6253 12 23 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one 55,isomer 7-(4-methoxybenzyl)-6-methyl-3- 20 10 17 18 1(2-methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 1 55, isomer 7-(4-methoxybenzyl)-6-methyl-3- 86 64 51 −13 2(2-methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 2 55, isomer 7-(4-methoxybenzyl)-6-methyl-3- 13 3 8 27 3(2-methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 3 55, isomer 7-(4-methoxybenzyl)-6-methyl-3- 137 208 131 14 (2-methyltetrahydrofuran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 4 56 7-(4-methoxybenzyl)-6-methyl-3- 65 21 43 7propylimidazo[1,5-a]pyrazin- 8(7H)-one 57 7-((6-methoxypyridin-3- 45 2684 −5 yl)methyl)-6-methyl-3- (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 58 6,7-dimethyl-3-(tetrahydro-2H-58% 1767 44% 36 pyran-4-yl)imidazo[1,5-a]pyrazin- (at 10 μM) (at 10 μM)8(7H)-one 59 7-ethyl-6-methyl-3-(tetrahydro- 2333 496 1737 −132H-pyran-4-yl)imidazo[1,5- a]pyrazin-8(7H)-one 606-methyl-7-propyl-3-(tetrahydro- 810 221 423 −132H-pyran-4-yl)imidazo[1,5- a]pyrazin-8(7H)-one 617-isopropyl-6-methyl-3-  4% 50% 47% 4 (tetrahydro-2H-pyran-4- (at 10 μM)(at 10 μM) (at 10 μM) yl)imidazo[1,5-a]pyrazin-8(7H)- one 627-isopentyl-6-methyl-3- 1078 558 93 7 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 63 7-(cyclopentylmethyl)-6-methyl-3-183 82 17 −3 (tetrahydro-2H-pyran-4- yl)imidazo[1,5-a]pyrazin-8(7H)- one64 2-((6-methyl-8-oxo-3-(tetrahydro- 624 528 103 112H-pyran-4-yl)imidazo[1,5- a]pyrazin-7(8H)- yl)methyl)benzonitrile 657-(cycloheptylmethyl)-6-methyl-3- 10 6 5 11 (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 69 7-(4-methoxybenzyl)-6-methyl-3-13 8 24 2 (3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 70 7-(4-methoxybenzyl)-6-methyl-3-29 17 28 −11 ((1R,2R,4S)-2-methyl-7- oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8(7H)- one 71 (S)-7-(4-methoxybenzyl)-6- 211238 538 13 methyl-3-(1- phenylethyl)imidazo[1,5- a]pyrazin-8(7H)-one 72(R)-7-(4-methoxybenzyl)-6- 90 12 43 9 methyl-3-(1-phenylethyl)imidazo[1,5- a]pyrazin-8(7H)-one 733-(1,4-dimethylpiperidin-4-yl)-7- 1923 1446 2450 nd (4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin- 8(7H)-one 74 3-(6-chloro-2,3-dihydro-1H- 52 3 −19 inden-1-yl)-7-(4-methoxybenzyl)- 6-methylimidazo[1,5-a]pyrazin-8(7H)-one 75 7-(4-methoxybenzyl)-6-methyl-3- 236 297 360 8(3-methyl-5-oxopyrrolidin-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one 763-(1-methoxy-2-methylpropan-2- 122 44 126 −14 yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin- 8(7H)-one 773-isopropyl-7-(4-methoxybenzyl)- 13 7 20 nd6-methylimidazo[1,5-a]pyrazin- 8(7H)-one 786-methyl-7-((2-methylthiazol-4- 1691 641 251 6yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,5-a]pyrazin- 8(7H)-one79 6-methyl-3-(tetrahydro-2H-pyran- 228 112 15 14 4-yl)-7-(thiophen-3-ylmethyl)imidazo[1,5-a]pyrazin- 8(7H)-one 806-methyl-3-(tetrahydro-2H-pyran- 72% 1310 496 18 4-yl)-7-(thiazol-4- (at10 μM) ylmethyl)imidazo[1,5-a]pyrazin- 8(7H)-one 817-((3,5-dimethylisoxazol-4- 27% 36% 2305 36 yl)methyl)-6-methyl-3- (at10 μM) (at 10 μM) (tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)- one 82 6-methyl-7-((5-methylisoxazol-3-67% 1498 1034 7 yl)methyl)-3-(tetrahydro-2H- (at 10 μM)pyran-4-yl)imidazo[1,5-a]pyrazin- 8(7H)-one 836-methyl-7-((3-methylisoxazol-5- 4444 2289 1606 −4yl)methyl)-3-(tetrahydro-2H- pyran-4-yl)imidazo[1,5-a]pyrazin- 8(7H)-one84 3-(2,6-dimethyltetrahydro-2H- 627 103 337 −5pyran-4-yl)-7-(4-methoxybenzyl)- 6-methylimidazo[1,5-a]pyrazin-8(7H)-one 85 7-(cyclohexylmethyl)-6-methyl-3- 120 32 32 7propylimidazo[1,5-a]pyrazin- 8(7H)-one 86 3-(2-hydroxypropan-2-yl)-7-(4-193 118 214 −11 methoxybenzyl)-6- methylimidazo[1,5-a]pyrazin- 8(7H)-one87 3-(2-fluoropropan-2-yl)-7-(4- 108 124 276 10 methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin- 8(7H)-one 887-(4-methoxybenzyl)-6-methyl-3- 484 308 548 −32(7-oxoazepan-4-yl)imidazo[1,5- a]pyrazin-8(7H)-one 897-(4-methoxybenzyl)-6-methyl-3- 65% 128 303 1(5-methyltetrahydrofuran-3- (at 10 μM) yl)imidazo[1,5-a]pyrazin-8(7H)-one 90 7-(4-methoxybenzyl)-6-methyl-3- 34 15 23 10(1-(4-methylthiazol-2- yl)ethyl)imidazo[1,5-a]pyrazin- 8(7H)-one 913-(7-(4-methoxybenzyl)-6-methyl- 181 185 417 208-oxo-7,8-dihydroimidazo[1,5- a]pyrazin-3-yl)-3-methylpyrrolidine-1-sulfonamide 92 6-(cyclopentylmethyl)-7-(4- 71 11 7957 methoxybenzyl)-3-(tetrahydro- 2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 93 3-(morpholino)-7-(4- 96 52 99 23methoxybenzyl)-6- methylimidazo[1,5-a]pyrazin- 8(7H)-one 947-(4-methoxybenzyl)-6-methyl-3- 2516 465 1231 −5 ((tetrahydrofuran-3-yl)amino)imidazo[1,5-a]pyrazin- 8(7H)-one 95 (R)-7-(4-methoxybenzyl)-6-258 162 218 9 methyl-3-(3- methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one 96 (S)-7-(4-methoxybenzyl)-6- 48 38 51 ndmethyl-3-(3- methylmorpholino)imidazo[1,5- a]pyrazin-8(7H)-one 977-(4-methoxybenzyl)-6-methyl-3- 202 82 128 −8(1,4-oxazepan-4-yl)imidazo[1,5- a]pyrazin-8(7H)-one 983-(2,2-dimethylmorpholino)-7-(4- 287 102 135 4 methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin- 8(7H)-one 99, isomer7-(3-fluorobenzyl)-3-(hexahydro- 241 134 27 9 14H-furo[3,2-b]pyrrol-4-yl)-6- methylimidazo[1,5-a]pyrazin- 8(7H)-one,isomer 1 99, isomer 7-(3-fluorobenzyl)-3-(hexahydro- 47% 760 119 6 24H-furo[3,2-b]pyrrol-4-yl)-6- (at 10 μM) methylimidazo[1,5-a]pyrazin-8(7H)-one, isomer 2 100, 7-(3-fluorobenzyl)-6-methyl-3- 306 223 43 11isomer 1 (tetrahydro-2H-pyran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 1 100, 7-(3-fluorobenzyl)-6-methyl-3- 333 93 33 −21 isomer2 (tetrahydro-2H-pyran-3- yl)imidazo[1,5-a]pyrazin-8(7H)- one,stereoisomer 2 nd means “not determined”

Table 1 lists the IC₅₀ value for inhibition of PDE1 by the compounds offormula (I). The IC₅₀ value refers to the concentration (nM) of thecompound required to reach 50% inhibition of the PDE1 enzyme at thespecified substrate concentration.

For certain compounds, the inhibition of PDE is listed as % inhibitionat a certain concentration.

For comparative purpose, the table also lists % inhibiton of PDE9 at 10μM.

PDE1 and PDE9 assays are described in the Experimental Section.

EXPERIMENTAL SECTION Preparation of the Compounds of Formula (I)

The compounds of Formula (I) may be prepared by methods described below,together with synthetic methods known in the art of organic chemistry,or modifications that are familiar to those of ordinary skill in theart. The starting materials used herein are available commercially ormay be prepared by routine methods known in the art, such as thosemethod described in standard reference books such as “Compendium ofOrganic Synthetic Methods, Vol. I-XII” (published withWiley-Interscience, ISSN: 1934-4783). Preferred methods include, but arenot limited to, those described below.

The schemes are representative of methods useful in synthesizing thecompounds of formula (I). They are not to constrain the scope of theinvention in any way. Unless otherwise indicated, in the reactionschemes and discussion that follow, R₁-R₄ are as defined in claim 1.

General Methods:

Method 1:

In brief, compounds of formula (I) can be prepared from the commercialavailable (3-chloropyrazin-2-yl)methanamine dihydrochloride V (CAS:867165-53-5). Reacting (3-chloropyrazin-2-yl)methanamine dihydrochlorideV with an acid derivative exemplified by but not limited to an acidchloride under conditions appropriate for amide formation, using a baseexemplified by but not limited to triethylamine and a solvent/solventmixture such as dimethylformamide and dichloromethane yields amide IV.Intermediate III can be prepared from IV by treatment with phosphorylchloride in a solvent such as dioxane. The8-chloroimidazo[1,5-a]pyrazine III is converted toimidazo[1,5-a]pyrazin-8(7H)-one II under standard hydrolysis conditionsexemplified by but not limited to hydrochloric acid in a solvent mixturesuch as water and 1,4-dioxane. Compound I is formed fromimidazo[1,5-a]pyrazin-8(7H)-one II by treatment with an alkylatingreagent exemplified by but not limited to an alkyl bromide using a baseexemplified but not limited to potassium carbonate in a solvent such asdimethylformamide.

Method 2:

In brief, compounds of formula (I) can be prepared from the commercialavailable 5-amino-3-methoxypyrazine-2-carbonitrile X (CAS:1137478-55-7). Reaction of 5-amino-3-methoxypyrazine-2-carbonitrile Xwith di-tert-butyl dicarbonate and a catalyst exemplified by but notlimited to N,N-dimethylpyridin-4-amine in a solvent such asdichloromethane gives pyrazine IX. Hydrogenation of IX with a catalystexemplified but not limited to Raney Nickel under an atmosphere ofhydrogen in a solvent such as methanol yields amine VIII. Compounds offormula VII can be prepared by employing compounds of formula VIII and acarboxylic acid using standard amide bond forming conditions exemplifiedbut not limited to HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate), a base, exemplified but not limited totriethylamine in a solvent such as dichloromethane. Boc protectedcompounds of formula VII can be deprotected to compounds of formula VIusing standard de-protection conditions exemplified by but not limitedto trifluoroacetic acid in a solvent such as dichloromethane. Treatingcompounds of formula VI with isoamyl nitrite, copper iodide anddiiodomethane in a solvent such as tetrahydrofuran yields compounds offormula V. Compounds of formula V can be converted to imidazopyrazinesof formula IV by treatment with phosphoryl chloride in a solvent such as1,4-dioxane. Imidazopyrazines of formula III are prepared from IV usingstandard cross coupling reaction conditions exemplified by but notlimited to a Suzuki-Miyaura cross-coupling reaction. Such conditions forthe cross coupling reaction are exemplified by but not limited to using;a boronic acid ester, potassium carbonate as the base, a mixture of1,4-dioxane and water as the solvent and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl₂) as the catalyst.Imidazo[1,5-a]pyrazin-8(7H)-ones of formula II are prepared by treatingcompounds of formula III with an acid exemplified but not limited tohydrochloric acid in a mixture of solvents such as water and methanol.Imidazo[1,5-a]pyrazin-8(7H)-ones of formula I are prepared by alkylationof II with an alkylating reagent exemplified by but not limited toalkylbromide using a base exemplified by but not limited to potassiumcarbonate in a solvent such as dimethylformamide.

Method 3:

In brief, compounds of formula (I) can be prepared from the commercialavailable methyl 1H-imidazole-5-carboxylate VI (CAS: 17325-26-7).Reaction of methyl 1H-imidazole-5-carboxylate VI with an α-halogenatedketone exemplified but not limited to an α-chloroketone, under theinfluence of a base exemplified but not limited to potassium carbonatein a solvent such as acetone yields the imidazole V. Treating imidazoleV with a brominating reagent exemplified but not limited toN-bromosuccinimide (NBS) in the presence of a radical initiatorexemplified by but not limited to azobisisobutyronitrile (AIBN) givesimidazole IV. Compounds of the formula III are formed by treatmentimidazole IV with ammonium acetate in a solvent such as 1,4-dioxane.Compounds of the formula II can be prepared from intermediate III usingstandard cross-coupling reaction conditions exemplified by but notlimited to a Suzuki-Miyaura cross-coupling reaction. Such conditions forthe cross-coupling reaction are exemplified by but not limited to using;a boronic acid ester, potassium carbonate as the base, a mixture of1,4-dioxane and water as the solvent and Pd(dppf)Cl₂ as the catalyst. Insome examples R₁ contains an unsaturated carbon-carbon bond which can bereduced by hydrogenation under conditions known to the person skilled inthe art. Imidazo[1,5-a]pyrazin-8(7H)-ones of formula I are prepared byalkylation of II with an alkylating reagent exemplified by but notlimited to alkylbromide using a base exemplified by but not limited topotassium carbonate in a solvent such as dimethylformamide.

Method 4:

In brief, compounds of formula (I) can be prepared from the commercialavailable 2-chloro-6-methylpyrazine X (CAS: 38557-71-0). Reacting2-chloro-6-methylpyrazine X with sodium methoxide in methanol yieldspyrazine IX. N-oxide VIII can be prepared from IX, by treatment with anoxidant, not limited to sodium metaborate and hydrogen peroxide, in asolvent such as acetic acid. Reacting VIII with a cyanide source, suchas trimethylsilyl cyanide and zinc(II)bromide, using a base exemplifiedby but not limited to triethylamine and a solvent/solvent mixture suchas acetonitrile yields cyanide VII. Reduction of VII, not limited toRaney nickel and hydrogen, in the presence of Boc-anhydride, producescarbamate VI. Amine V can be liberated by use of trifluoro acetic acid,but not limited to, from VI. Reacting amine V with an acid derivativeexemplified by but not limited to an acid chloride under conditionsappropriate for amide formation, using a base exemplified by but notlimited to triethylamine and a solvent/solvent mixture such asdimethylformamide and dichloromethane yields amide IV. Intermediate IIIcan be prepared from IV by treatment with phosphoryl chloride in asolvent such as dioxane. The 8-chloroimidazo[1,5-a]pyrazine III isconverted to imidazo[1,5-a]pyrazin-8(7H)-one II under standardhydrolysis conditions exemplified by but not limited to hydrochloricacid in a solvent mixture such as water and 1,4-dioxane. Compound I isformed from imidazo[1,5-a]pyrazin-8(7H)-one II by treatment with analkylating reagent exemplified by but not limited to an alkyl bromideusing a base exemplified but not limited to potassium carbonate in asolvent such as dimethylformamide.

Analytical Methods

Analytical LC-MS data were obtained using the methods identified below.

Method 1:

An Agilent 1200 LCMS system with ELS detector was used. Column: XBridgeShieldRP18, 5 μm, 50×2.1 mm; Column temperature: 40° C.; Solvent system:A=water/NH₃*H₂O (99.95:0.05) and B=acetonitrile; Method: Linear gradientelution with A:B=99:1 to 0:100 in 3.4 minutes and with a flow rate of0.8 mL/min.

Method 2:

A Shimadzu 20 MS instrument equipped with atmospheric pressure photoionisation ion source and a Shimadzu LC-20AB system was used. Column:MERCK, RP-18e 25-2 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9625:0375) andB=acetonitrile/trifluoroacetic acid (99.981:0.019); Method: A lineargradient elution A:B=95:5 to A:B=5:95 in 0.7 minutes, then A:B=5:95 for0.4 minutes, then with a linear gradient elution to A:B 95:5 for 0.4minutes with a constant flow rate of 1.5 mL/min.

Method 3:

An Agilent 1200 LCMS system with ELS detector was used. Column: AgilentTC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method 4:

An Agilent 1200 LCMS system with ELS detector was used. Column: AgilentTC-C18 5 μm; 2.1×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method 5:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7 μm;2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutes and witha flow rate of 1.2 mL/minute.

Method 6:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7 μm;2.1×50 mm; Column temperature: 60° C.; Solvent system: A=water/formicacid (99.9:0.1) and B=acetonitrile/water/formic acid (94.9:5:0.1);Method: Linear gradient elution with A:B=90:10 to 0:100 in 1.0 minutesand with a flow rate of 1.2 mL/minute.

Method 7:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC HSS T3 C18 1.8μm; 2.1×50 mm; Column temperature: 60° C.; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=98:02 to 0:100 in 1.0 minutes and witha flow rate of 1.2 mL/min.

Method 8:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method 9:

An Agilent 1200 LCMS system with ELS detector was used. Column: XtimateC18 2.1*30 mm, 3 um; 2.0×50 mm; Column temperature: 50° C.; Solventsystem: A=water/trifluoroacetic acid (99.9996:0.0004) andB=acetonitrile/trifluoroacetic acid (99.9998:0.0002); Method: Lineargradient elution with A:B=100:0 to 70:30 in 3.0 minutes and with a flowrate of 0.8 mL/min.

Method 10:

An Agilent 1200 LCMS system with ELS detector was used. Column: XtimateC18 2.1*30 mm, 3 um; 2.0×50 mm; Column temperature: 50° C.; Solventsystem: A=water/trifluoroacetic acid (99.9996:0.0004) andB=acetonitrile/trifluoroacetic acid (99.9998:0.0002); Method: Lineargradient elution with A:B=100:0 to 40:60 in 1.5 minutes and with a flowrate of 1.2 mL/min.

Method 11:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1*50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=95:5 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method 12:

An Agilent 1100 LCMS system with ELS detector was used. Column: YMCODS-AQ 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 5:95 in 3.5 minutes and with a flowrate of 0.8 mL/min.

Method 13:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=99:1 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method 14:

An Agilent 1200 LCMS system with ELS detector was used. Column: XtimateC18 2.1*30 mm, 3 um; 2.0×50 mm; Column temperature: 50° C.; Solventsystem: A=water/trifluoroacetic acid (99.9996:0.0004) andB=acetonitrile/trifluoroacetic acid (99.9998:0.0002); Method: Lineargradient elution with A:B=100:0 to 40:60 in 6.0 minutes and with a flowrate of 0.8 mL/min.

Method 15:

An Agilent 1200 LCMS system with ELS detector was used. Column: MERCK,RP-18e 25-2 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9996:0.0004) andB=acetonitrile/trifluoroacetic acid (99.9998:0.0002); Method: Lineargradient elution with A:B=95:5 to 5:95 in 0.7 minutes and with a flowrate of 1.5 mL/min.

Method 16:

An Agilent 1200 LCMS system with ELS detector was used. Column: XtimateC18 2.1*30 mm, 3 um; 2.0×50 mm; Column temperature: 50° C.; Solventsystem: A=water/trifluoroacetic acid (99.9996:0.0004) andB=acetonitrile/trifluoroacetic acid (99.9998:0.0002); Method: Lineargradient elution with A:B=100:0 to 40:60 in 0.9 minutes and with a flowrate of 1.2 mL/min.

Method 17:

An Agilent 1200 LCMS system with ELS detector was used. PhenomenexLuna-C18, 5 μm; 2.0×50 mm; Column temperature: 50° C.; Solvent system:A=water/trifluoroacetic acid (99.9:0.1) andB=acetonitrile/trifluoroacetic acid (99.95:0.05); Method: Lineargradient elution with A:B=90:10 to 0:100 in 4.0 minutes and with a flowrate of 0.8 mL/min.

Method 18:

An Agilent 1200 LCMS system with ELS detector was used. Column: WatersXBridge ShieldRP18, 2.1*50 mm, 5 μm; Column temperature: 40° C.; Solventsystem: A=water/ammonia (99.95:0.05) and B=acetonitrile; Method: Lineargradient elution with A:B=85:15 to 0:100 in 3.4 minutes and with a flowrate of 0.8 mL/min.

Method 19:

A Waters Acquity UPLC-MS was used. Column: Acquity UPLC BEH C18 1.7 μm;2.1×50 mm; Column temperature: 60° C.; Solvent system: A=water/formicacid (99.9:0.1) and B=acetonitrile/water/formic acid (94.9:5:0.1);Method: Linear gradient elution with A:B=98:2 to 0.1:99.9 in 1.0 minutesand with a flow rate of 1.2 mL/minute.

Preparative LC-MS-purification was performed on a PE Sciex API 150EXinstrument with atmospheric pressure chemical ionization. Column: 50×20mm YMC ODS-A with 5 μm particle size; Solvent system:A=water/trifluoroacetic acid (99.965:0.035) andB=acetonitrile/water/trifluoroacetic acid (94.965:5:0.035); Method:Linear gradient elution with A:B=80:20 to 0:100 in 7 minutes and with aflow rate of 22.7 mL/minute. Fraction collection was performed bysplit-flow MS detection.

Preparative SFC was performed on a Thar 80 instrument. Exemplifiedconditions can be, but not limited to: Column AD 250×30 mm with 20 μmparticle size; Column temperature: 38° C., Mobile phase: SupercriticalCO₂/EtOH (0.2% NH₃H₂O)=45/55.

Intermediates N-((3-chloropyrazin-2-yl)methyl)butyramide

To an ice-cold solution of (3-chloropyrazin-2-yl)methanamine (2.0 g, 14mmol) in dichloromethane (50 mL) and dimethylformamide (10 mL) was addedtriethylamine (4.5 g, 45 mmol), followed by butyryl chloride (2.0 g, 14mmol). The reaction was allowed to warm to room temperature and stirredfor 1 hour. The reaction mixture was quenched with water and extractedwith dichloromethane (2×250 mL). The combined organic phases were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to affordN-((3-chloropyrazin-2-yl)methyl)butyramide 2.4 g (81%).

8-Chloro-3-propylimidazo[1,5-a]pyrazine

To a solution of N-((3-chloropyrazin-2-yl)methyl)butyramide (2.4 g, 11mmol) in 1,4-dioxane (20 mL) was added POCl₃ (3.44 g, 22.5 mmol). Themixture was stirred at 100° C. for 2 hrs and then cooled on an ice-bath.Saturated. aq. NaHCO₃ was added carefully and the mixture was extractedwith dichloromethane (2×50 mL). The combined organic phases were washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to give8-chloro-3-propylimidazo[1,5-a]pyrazine 2 g (63%).

3-Propylimidazo[1,5-a]pyrazin-8(7H)-one

A solution of 3-propylimidazo[1,5-a]pyrazin-8(7H)-one (100 mg, 0.51mmol) in a mixture of 1,4-dioxane (10 mL) and H₂O (4 mL) was stirred at100° C. for 2 hours. The reaction mixture was concentrated in vacuo andthe residue was diluted with dichloromethane (50 mL), washed withNaHCO₃(aq), then brine, dried over Na₂SO₄ and concentrated in vacuo togive 3-propylimidazo[1,5-a]pyrazin-8(7H)-one 50 mg (55%).

Methyl 1-(2-oxopropyl)-1H-imidazole-5-carboxylate

A mixture of methyl 1H-imidazole-5-carboxylate (20 g, 0.16 mol),1-chloropropan-2-one (22 g, 0.24 mol), and potassium carbonate (44 g,0.32 mol) in acetone (400 mL) was stirred at 30° C. for 12 hours. Thereaction mixture was concentrated in vacuo, the residue was diluted withethyl acetate (200 mL) and washed with H₂O (3×50 mL). The organic layerwas dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography using a gradient of petroleum ether andethyl acetate to give methyl 1-(2-oxopropyl)-1H-imidazole-5-carboxylate10 g (35%).

Methyl 2-bromo-1-(2-oxopropyl)-1H-imidazole-5-carboxylate

A mixture of methyl 1-(2-oxopropyl)-1H-imidazole-5-carboxylate (10 g, 55mmol), N-bromosuccinimide (12.7 g, 71.4 mmol) and azobisisobutyronitrile(1.8 g, 11 mmol) in chloroform (100 mL) was stirred at 50° C. for 12hours. The mixture was concentrated in vacuo. The residue was purifiedby flash chromatography using a gradient of petroleum ether and ethylacetate to give methyl2-bromo-1-(2-oxopropyl)-1H-imidazole-5-carboxylate 13 g (91%).

3-Bromo-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

A mixture of methyl 2-bromo-1-(2-oxopropyl)-1H-imidazole-5-carboxylate(14 g, 50 mmol) and ammonium acetate (16.5 g, 215 mmol) in 1,4-dioxane(150 mL) was stirred at 60° C. for 12 hours. The mixture was thenstirred at 90° C. for another 24 hours. The reaction mixture wasconcentrated in vacuo and the residue was diluted with ethyl acetate(600 mL) and washed with water (3×100 mL). The combined organic phaseswere dried with anhydrous Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography using a gradient of petroleum etherand ethyl acetate to give3-bromo-6-methylimidazo[1,5-a]pyrazin-8(7H)-one 4.8 g (39%).

3-(3,6-Dihydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

A mixture of 3-bromo-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (4.5 g, 20mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4.97 g, 23.7 mmol), Pd(dppf)Cl₂ (2.9 g, 3.95 mmol), potassium carbonate(5.5 g, 39 mmol) and H₂O (10 mL) in 1,4-dioxane (40 mL) was stirred at100° C. for 12 hours. The mixture was filtred and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyusing a gradient of dichloromethane and methanol to give3-(3,6-dihydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one4.0 g (88%).

6-Methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of3-(3,6-dihydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(4.0 g, 17 mmol) and 10% Pd/C (300 mg) in tetrahydrofuran (15 mL) wasstirred at 15° C. for 7 hrs under an atmosphere of hydrogen. Thereaction mixture was filtered and the filtrate was concentrated in vacuoto afford6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 3.5g (87%).

Tert-butyl (5-cyano-6-methoxypyrazin-2-yl)carbamate

A solution of 5-amino-3-methoxypyrazine-2-carbonitrile (4.70 g, 31.3mmol), di-tert-butyl dicarbonate (8.9 g, 41 mmol),N,N-dimethylpyridin-4-amine (38 mg, 0.31 mmol) in dichloromethane (150mL) was stirred at 3000 for 12 hours. The reaction mixture wasconcentrated in vacuo. The residue was purified by flash chromatographyusing a gradient of petroleum ether and ethyl acetat to affordtert-butyl (5-cyano-6-methoxypyrazin-2-yl)carbamate 9.0 g (80%).

Tert-butyl (5-(aminomethyl)-6-methoxypyrazin-2-yl)carbamate

A mixture of tert-butyl (5-cyano-6-methoxypyrazin-2-yl)carbamate (9.0 g,36 mmol), Raney Ni 40-60 mesh (5 g) and sat. NH₃ in methanol (2 mL) inmethanol (100 mL) was stirred at 30° C. for 12 hrs under H₂ (45 psi).The reaction was filtered and concentrated in vacuo to afford tert-butyl(5-(aminomethyl)-6-methoxypyrazin-2-yl)carbamate 10 g, sufficiently purefor the next step.

Tert-butyl(6-methoxy-5-((tetrahydro-2H-pyran-4-carboxamido)methyl)pyrazin-2-yl)carbamate

A solution of tert-butyl(5-(aminomethyl)-6-methoxypyrazin-2-yl)carbamate (10.0 g, 31.5 mmol),tetrahydro-2H-pyran-4-carboxylic acid (4.50 g, 34.6 mmol), triethylamine(6.37 g, 62.9 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluoro phosphate (13.2 g, 34.6 mmol) in dichloromethane (120mL) was stirred at 30° C. for 12 hours. The reaction mixture wasconcentrated in vacuo and the residue was purified by flashchromatography using a gradient of petroleum ether and ethyl acetate toafford tert-butyl(6-methoxy-5-((tetrahydro-2H-pyran-4-carboxamido)methyl)pyrazin-2-yl)carbamate8 g (69.4%).

N-((5-Amino-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

A solution of tert-butyl(6-methoxy-5-((tetrahydro-2H-pyran-4-carboxamido)methyl)pyrazin-2-yl)carbamate(8 g, 21.8 mmol) and trifluoroacetic acid (40 mL) in dichloromethane (40mL) was stirred at 30° C. for 12 hours. The reaction mixture wasconcentrated in vacuo. The residue was diluted with dichloromethane (100mL), and washed with NaHCO₃ until pH=8. The organic layer was washedwith water (3×20 mL), dried and concentrated in vacuo. The residue waspurified by flash chromatography using a gradient of petroleum ether andethyl acetate to yieldN-((5-amino-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide4 g (65.4%).

N-((5-Iodo-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

A solution ofN-((5-amino-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide(2.40 g, 9.01 mmol), copper(I)iodide (1.72 g, 9.01 mmol), isoamylnitrite (1.58 g, 13.5 mmol) and diiodomethane (2.41 g, 9.01 mmol) intetrahydrofuran (50 mL) was stirred at 75° C. for 6 hours. The mixturewas filtered and concentrated in vacuo. The residue was purified byflash chromatography using a gradient of petroleum ether and ethylacetate to affordN-((5-iodo-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide2.20 g (64.7%).

6-Iodo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine

To a solution ofN-((5-iodo-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide(2 g, 5.30 mmol) in 1,4-dioxane (60 mL) was added phosphoryl chloride(8.13 g, 53.0 mmol) at 000° C. The reaction was stirred at 85° C. for 12hours. The mixture was concentrated in vacuo. The residue was dilutedwith dichloromethane (100 mL) and ice-water (60 mL), followed bysaturated aqueous NaHCO₃ (30 mL). The organic phase was separated andthe water phase was extracted with dichloromethane (3×20 mL). Thecombined organic phases were dried and concentrated in vacuo. Theresidue was purified by flash chromatography using a gradient ofpetroleum ether and ethyl acetate to yield6-iodo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine 500mg (23.6%).

6-Benzyl-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine

A mixture of6-iodo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (500mg, 1.39 mmol), 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (911mg, 4.18 mmol), Pd(dppf)Cl₂ (51 mg, 0.07 mmol), K₂CO₃ (577 mg, 4.18mmol) and H₂O (3 mL) in 1,4-dioxane (15 mL) was stirred at 80° C. for 12hrs under an atmosphere of N₂. It was then filtred and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyusing a gradient of petroleum ether and ethyl acetate to yield6-benzyl-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine260 mg (52%).

6-Benzyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A solution of6-benzyl-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine(320 mg, 0.990 mmol) and 2 M aq. HCl (8 mL) in methanol (20 mL) wasstirred at 60° C. for 12 hours. The solution was concentrated in vacuo.The residue was purified by flash chromatography using a gradient ofpetroleum ether and ethyl acetate to yield6-benzyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 230mg (68%).

N-((3-chloropyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

To a solution of (3-chloropyrazin-2-yl)methanamine dihydrochloride (3.8g, 18 mmol) in anhydrous DMF (20 mL) was added triethylamine (5.7 g, 56mmol). The mixture was cooled to 0° C., tetrahydro-2H-pyran-4-carbonylchloride (2.9 g, 19 mmol) was added dropwise. The mixture was stirred at0° C. for 0.5 hours. The reaction mixture was diluted with water (50 mL)and extracted with ethyl acetate (3×80 mL). The combined organic phaseswere washed with brine (50 mL), dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography eluting withethyl acetate to affordN-((3-chloropyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide 2.4 g(54%). 8-Chloro-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine:

To a solution ofN-((3-chloropyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide (2.5g, 9.8 mmol) in anhydrous 1,4-dioxane (20 mL) was added phosphorylchloride (3.4 g, 22 mmol). The reaction was stirred at 80° C. for 2hours. Then the solution was cooled and poured into water (100 mL), pHwas adjusted to 8-9 by the addition of saturated aqueous K₂CO₃. Thecrude mixture was extracted with ethyl acetate (2×100 mL). The combinedorganic phases were washed with brine (50 mL), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatographyusing a gradient of petroleum ether and ethyl acetate to yield8-chloro-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine 2.1 g (90%).

3-(Tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of8-chloro-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (2.1 g, 8.8mmol) in 1,4-dioxane (20 mL) was added 2 M aq. HCl (10 mL). The solutionwas stirred at 80° C. for 2 hours. The mixture was cooled and pH wasadjusted to 8-9 by addition of saturated aqueous K₂CO₃. The crudemixture was concentrated in vacuo and the residue was dissolved inmethanol (150 mL) and filtered. The filtrate was concentrated in vacuoand the residue was purified by flash chromatography using a mixture ofdichloromethane and methanol (10:1) to give3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 1.6 g (81%).

¹H NMR (DMSO-d₆, 400 MHz): δ 10.55 (s, 1H), 7.63 (s, 1H), 7.39 (d, J=6.0Hz, 1H), 6.60 (s, 1H), 3.91-3.88 (m, 2H), 3.49-3.42 (m, 2H), 3.34-3.29(m, 1H), 1.82-1.72 (m, 4H).

LC-MS: (m/z) 220.1 (MH⁺) t_(R) (minutes, method 3)=1.37 minutes

N-((3-Chloropyrazin-2-yl)methyl)cyclopropanecarboxamide

To a solution of of (3-chloropyrazin-2-yl)methanamine dihydrochloride(4.0 g, 19 mmol) in anhydrous DMF (20 mL) was added Et₃N (1.9 g, 18.5mmol). The mixture was cooled to 0° C. and cyclopropanecarbonyl chloride(2.3 g, 22 mmol) was added dropwise. The reaction was stirred at 0° C.for 0.5 hours. The reaction mixture was diluted with water (50 mL),extracted with ethyl acetate (2×100 mL). The combined organic phaseswere washed with brine (40 mL), dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography eluting withpetroleum ether/ethyl acetate 2/1 to yieldN-((3-chloropyrazin-2-yl)methyl)cyclopropanecarboxamide 3.3 g (85%).

8-Chloro-3-cyclopropylimidazo[1,5-a]pyrazine

To a solution of N-((3-chloropyrazin-2-yl)methyl)cyclopropanecarboxamide(3.3 g, 15.6 mmol) in anhydrous 1,4-dioxane (30 mL) was added phosphorylchloride (5.3 g, 35 mmol). The reaction was stirred at 80° C. for 2hours. Then the solution was cooled on an ice-bath and poured into water(50 mL). The pH was adjusted to 8-9 by addition of saturated aqueousK₂CO₃. The mixture was extracted with ethyl acetate (2×50 mL). Thecombined organic phases were washed with brine (50 mL), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography using petroleum ether/ethyl acetate 3:1 to yield8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine 2.4 g (80%).

3-Cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 8-chloro-3-cyclopropylimidazo[1,5-a]pyrazine (2.5 g, 13mmol) in 1,4-dioxane (20 mL) was added 2 M aq. HCl (10 mL). The solutionwas stirred at 80° C. for 2 hrs. The mixture was cooled on an ice-bathand pH adjusted to 8-9 by addition of saturated aqueous K₂CO₃. Themixture was concentrated in vacuo and the residue was dissolved inmethanol (150 mL) and filtered. The filtrate was concentrated in vacuoand the residue was purified by flash chromatography usingdichloromethane/methanol (10/1) to afford3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one 1.9 g (83%).

¹H NMR (DMSO-d₆, 400 MHz): δ10.49 (s, 1H), 7.54 (s, 1H), 7.41 (d, J=5.6Hz, 1H), 6.61 (d, J=5.6 Hz, 1H), 2.29-2.24 (m, 1H), 0.99-0.89 (m, 4H).

LC-MS: (m/z) 176.1 (MH⁺) t_(R) (minutes, method 1)=1.04 minutes

N-((5-Bromo-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide

A solution of NaNO₂ (972 mg, 14.09 mmol) in H₂O (100 mL) was added to astirred solution ofN-((5-amino-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide(2.5 g, 9.4 mmol) in 40% aq. HBr (33 mL) at 0° C. After stirring for 1.5hrs, CuBr (2.02 g, 14.1 mmol) was added and the mixture was stirred at70° C. for 1 hour. The pH value was adjusted to pH 8 by addition ofsaturated aqueous NaHCO₃. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyusing a gradient of petroleum ether and ethyl acetate to yieldN-((5-bromo-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide800 mg (25%).

LC-MS: (m/z) 331.8 (MH⁺) t_(R) (minutes, method 2)=0.723 minutes

6-Bromo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine

To a solution ofN-((5-bromo-3-methoxypyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide(800 mg, 2.42 mmol) in 1,4-dioxane (30 mL) was added phosphoryl chloride(3.8 g, 25 mmol) at 0° C. The mixture was heated to 70° C. and stirredfor 1 hour. The mixture was concentrated in vacuo and the residue wasdiluted with dichloromethane (100 mL) and ice-water (60 mL). The pHvalue was adjusted to pH 8 by addition of saturated aqueous NaHCO₃. Theorganic phase was separated and aqueous phase was extracted withdichloromethane (3×30 mL). The combined organic phases were dried andconcentrated in vacuo. The residue was purified by flash chromatographyusing a gradient of dichloromethane and methanol to yield6-bromo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine 500mg (66%).

LC-MS: (m/z) 313.7 (MH⁺) t_(R) (minutes, method 2)=0.740 minutes

6-Bromo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of6-bromo-8-methoxy-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine(200 mg, 0.641 mmol) in dichloromethane (30 mL) was added borontribromide (1.61 g, 6.41 mmol) at 0° C. The reaction was warmed to 20°C. and stirred for 3 hours. The solution was quenched with water (2 mL)at 0° C. The reaction was concentrated in vacuo and the residue waspurified by flash chromatography using a gradient of dichloromethane andmethanol to yield6-bromo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one 130mg (68%).

LC-MS: (m/z) 299.7 (MH⁺) t_(R) (minutes, method 2)=0.730 minutes

2-methoxy-6-methylpyrazine

To a suspension of 2-chloro-6-methylpyrazine (24 g, 186.7 mmol) inanhydrous MeOH (240 mL) was added NaOMe (12.1 g, 224 mmol). The mixturewas stirred at 60-70° C. for 16 hours. The mixture was cooled andfiltered. The filtrate was concentrated in vacuo to give2-methoxy-6-methylpyrazine (22 g, 95% yield). ¹H NMR (CDCl₃400 MHz): δ7.98 (s, 1H), 7.94 (s, 1H), 3.91 (s, 3H), 3.40 (s, 3H). LC-MS:t_(R)=1.47 min (method 14), m/z=124.8 [M+H]⁺.

3-methoxy-5-methylpyrazine 1-oxide

To a solution of 2-methoxy-6-methylpyrazine (21.3 g, 171.6 mmol) in AcOH(150 mL) was added NaBO₂—H₂O₂.3H₂O (31.7 g, 205.9 mmol). The mixture wasstirred at 80° C. for 16 hours. The mixture was concentrated in vacuoand diluted with 2 M aq. NaOH (300 mL). The mixture was extracted withEtOAc (200 mL×4). The organic layer was washed with brine (100 mL),dried over Na₂SO₄ and concentrated in vacuo to give3-methoxy-5-methylpyrazine 1-oxide (14.4 g, 60% yield).

3-methoxy-5-methylpyrazine-2-carbonitrile

To a mixture of 3-methoxy-5-methylpyrazine 1-oxide (10 g, 71.4 mmol) inMeCN (200 mL) was added TMSCN (24.8 g, 249.8 mmol) and triethylamine(36.1 g, 356.8 mmol), ZnBr₂ (32.1 g, 142.7 mmol). The mixture wasstirred at 85-90° C. for 16 hours. The mixture was concentrated invacuo. The residue was diluted with DCM (500 mL) and filtered. Thefiltrate was washed with water (300 mL) and brine (200 mL). The organiclayer was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=5:1) to give 3-methoxy-5-methylpyrazine-2-carbonitrile (4.1 g,38% yield).

tert-butyl ((3-methoxy-5-methylpyrazin-2-yl)methyl)carbamate

To a solution of 3-methoxy-5-methylpyrazine-2-carbonitrile (6.22 g, 41.7mmol) in MeOH (100 mL) was added (Boc)₂O (13.65 g, 62.6 mmol) and RaneyNi (2.0 g). The mixture was stirred at 20-25° C. under H₂ (45 psi) for16 hours. The mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=5:1) to give tert-butyl((3-methoxy-5-methylpyrazin-2-yl)methyl)carbamate (7.7 g, 72% yield).

LC-MS: t_(R)=0.70 min (method 15), m/z=254.0 [M+H]⁺.

(3-methoxy-5-methylpyrazin-2-yl)methanamine

To a solution of tert-butyl((3-methoxy-5-methylpyrazin-2-yl)methyl)carbamate (7.7 g, 30.3 mmol) inTHF (50 mL) was added TFA (20 mL). The mixture was stirred at 80° C. for2 hours. The mixture was concentrated in vacuo. The residue was dilutedwith 2 M aq. NaOH (200 mL), extracted with DCM (100 mL×2). The organiclayer was washed with brine (50 mL), dried over Na₂SO₄ and concentratedin vacuo to give (3-methoxy-5-methylpyrazin-2-yl)methanamine (2.5 g, 54%yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.90 (s, 1H), 3.96 (s, 3H), 3.93 (s, 2H), 2.42(s, 3H), 1.69 (s, 2H).

LC-MS: t_(R)=0.73 min(method 16), m/z=154.2 [M+H]⁺.

Compounds of Formula (I) Example 1

7-(3-Fluorobenzyl)-3-propylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 3-propylimidazo[1,5-a]pyrazin-8(7H)-one (1.2 g, 6.8mmol) in DMF (10 mL) was added potassium carbonate (1.4 g, 10 mmol) and1-(bromomethyl)-3-fluorobenzene (1.54 g, 8.13 mmol). The mixture wasstirred at 60-70° C. for 2 hrs and then cooled to room temperature. Tothe reaction was added water (75 mL) and it was extracted with ethylacetate (2×50 mL). The combined organic phases were washed with brine,dried and concentrated in vacuo. The residue purified by flashchromatography to yield 1.5 g (78%) of7-(3-fluorobenzyl)-3-propylimidazo[1,5-a]pyrazin-8(7H)-one.

¹H NMR (DMSO-d₆, 400 MHz): δ7.70 (s, 1H), 7.46-7.37 (m, 2H), 7.17-7.09(m, 3H), 7.00 (d, J=6.0 Hz, 1H), 5.02 (s, 2H), 2.83 (t, 2H), 1.75-1.66(m, 2H), 0.91 (t, 3H).

LC-MS: (m/z) 286.1 (MH⁺) t_(R) (minutes, method 3)=2.19 minutes

Example 2

6-Benzyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-benzyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 0.647 mmol), 1-(bromomethyl)-3-fluorobenzene (159 mg, 840 μmol)and potassium carbonate (179 mg, 1.29 mmol) in DMF (6 mL) was stirred at60° C. for 12 hours. The reaction mixture was concentrated in vacuo andthe residue was diluted with dichloromethane (20 mL) and washed withwater (3×5 mL). The combined organic phases were dried, filtered andconcentrated in vacuo. The residue was purified by preparative TLC,eluting with petroleum ether and ethyl acetate 1:2, to yield6-benzyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one80 mg (28%).

¹H NMR (CDCl₃, 400 MHz): δ7.97 (s, 1H), 7.39-7.30 (m, 4H), 7.17 (d,J=7.53 Hz, 2H), 6.94-6.92 (m, 2H), 6.83 (d, J=9.54 Hz, 1H), 6.74 (s,1H), 5.06 (s., 2H), 4.12 (d, J=12.05 Hz, 2H), 3.74 (s, 2H), 3.58-3.52(m, 2H), 3.03-3.09 (m, 1H), 2.19-2.09 (m, 2H), 1.89 (d, J=13.55 Hz, 2H).

LC-MS: (m/z) 418.2 (MH⁺) t_(R) (minutes, method 3)=2.69 minutes

Example 3

6-Benzyl-7-(cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-benzyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (60mg, 0.19 mmol), (bromomethyl)cyclohexane (52 mg, 0.29 mmol) andpotassium carbonate (54 mg, 0.39 mmol) in DMF (10 mL) was stirred at 75°C. for 12 hours. The reaction mixture was concentrated in vauo. Theresidue was diluted with dichloromethane (20 mL) and washed with water(3×5 mL). The combined organic phases were dried, filtered andconcentrated in vacuo. The residue was purified by preparative TLC,eluting with petroleum ether and ethyl acetate 1:2, to yield6-benzyl-7-(cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one15 mg (8.1%).

¹H NMR (CDCl₃, 400 MHz): δ7.87 (s, 1H), 7.42-7.30 (m, 3H), 7.19 (d,J=7.34 Hz, 2H), 6.65 (s, 1H), 4.11 (d, J=11.25 Hz, 2H), 3.90 (s, 2H),3.66 (d, J=6.36 Hz, 2H), 3.54 (t, J=10.76 Hz, 2H), 3.05-2.99 (m, 1H),2.18-2.04 (m, 2H), 1.86 (d, J=13.94 Hz, 2H), 1.63-1.77 (m, 7H),1.18-1.15 (m, 2H), 1.04-1.01 (m, 2H).

LC-MS: (m/z) 406.2 (MH⁺) t_(R) (minutes, method 4)=2.38 minutes

Example 4

7-(Cyclohexylethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (50mg, 0.21 mmol), (bromomethyl)cyclohexane (57 mg, 0.32 mmol) andpotassium carbonate (59 mg, 0.43 mmol) in DMF (2 mL) was stirred at 60°C. for 12 hours. The reaction mixture was concentrated in vacuo. Theresidue was diluted with dichloromethane (20 mL) and washed with water(3×5 mL). The combined organic phases were dried, filtered andconcentrated in vacuo. The residue was purified by preparative LC-MS toyield7-(cyclohexylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one20 mg (28%), ¹H NMR (CDCl₃, 400 MHz): δ 7.85 (s, 1H), 6.71 (s, 1H), 4.13(d, J=11.04 Hz, 2H), 3.78 (d, J=7.03 Hz, 2H), 3.66-3.53 (m, 2H),3.11-3.05 (m, 1H), 2.27 (s, 3H), 2.20-2.05 (m, 2H), 1.88 (d, J=12.05 Hz,2H), 1.80-1.64 (m, 6H), 1.25-1.13 (m, 3H), 1.12-0.99 (m, 2H).

LC-MS: (m/z) 330.2 (MH⁺) t_(R) (minutes, method 3)=2.49 minutes

Example 5

7-(3-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (50mg, 0.21 mmol), 1-(bromomethyl)-3-fluorobenzene (60 mg, 0.32 mmol) andK₂CO₃ (59 mg, 0.43 mmol) in DMF (2 mL) was stirred at 60° C. for 12hours. The reaction mixture was concentrated in vacuo. The residue wasdiluted with dichloromethane (20 mL) and washed with water (3×5 mL). Theorganic layer was dried and concentrated in vacuo. The residue waspurified by preparative LC-MS to give7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one20 mg (27%).

¹H NMR (CDCl₃, 400 MHz): δ 7.94 (s, 1H), 7.34-7.29 (m, 1H), 7.03-6.94(m, 2H), 6.90 (d, J=9.70 Hz, 1H), 6.77 (s, 1H), 5.23 (s, 2H), 4.14 (d,J=10.14 Hz, 2H), 3.59 (td, J=11.69, 1.76 Hz, 2H), 3.15-3.05 (m, 1H),2.18 (s, 3H), 2.17-2.08 (m, 2H), 1.90 (d, J=13.45 Hz, 2H).

LC-MS: (m/z) 342.2 (MH⁺) t_(R) (minutes, method 3)=2.34 minutes

Example 6

3-Cyclopropyl-7-(3-fluorobenzyl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one (300 mg,1.71 mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (355 mg, 2.57 mmol)and 1-(bromomethyl)-3-fluorobenzene (388 mg, 2.05 mmol). The mixture wasstirred at 65° C. for 16 hours. The mixture was filtered and thefiltrate was purified by preparative-HPLC to yield3-cyclopropyl-7-(3-fluorobenzyl)imidazo[1,5-a]pyrazin-8(7H)-one 280 mg(58%).

¹H NMR (DMSO-d₆ 400 MHz): δ 7.59-7.56 (m, 2H), 7.36-7.33 (m, 1H),7.13-7.09 (m, 3H), 6.98 (d, J=6.0 Hz, 1H), 4.98 (s, 2H), 2.29-2.24 (m,1H), 1.00-0.90 (m, 4H).

LC-MS: (m/z) 284.1 (MH⁺) t_(R) (minutes, method 3)=2.23 minutes

Example 7

7-(Cyclopentylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one (300 mg,1.71 mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (355 mg, 2.57 mmol)and (bromomethyl)cyclopentane (335 mg, 2.05 mmol). The reaction wasstirred at 65° C. for 16 hours. The mixture was filtered and thefiltrate was purified by preparative LC-MS to yield7-(cyclopentylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one 210mg (47%).

¹H NMR (DMSO-d₆, 400 MHz): δ 7.53 (s, 1H), 7.51 (d, J=6.0 Hz, 1H), 6.90(d, J=6.0 Hz, 1H), 3.69 (d, J=7.6 Hz, 2H), 2.29-2.24 (m, 2H), 1.58-1.45(m, 6H), 1.22-1.19 (m, 2H), 1.00-0.89 (m, 4H).

LC-MS: (m/z) 258.2 (MH⁺) t_(R) (minutes, method 3)=2.24 minutes

Example 8

7-(Cyclohexylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one (300 mg,1.71 mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (355 mg, 2.57 mmol)and (bromomethyl)cyclohexane (363 mg, 2.05 mmol). The reaction wasstirred at 65° C. for 16 hours. The reaction mixture was filtered andthe filtrate was purified by preparative LC-MS to yield7-(cyclohexylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one 195 mg(42%).

¹H NMR (DMSO-d₆, 400 MHz): δ7.53-7.49 (m, 2H), 6.84 (d, J=6.0 Hz, 1H),3.59 (d, J=7.6 Hz, 2H), 2.27-2.25 (m, 1H), 1.68-1.55 (m, 6H), 1.10-0.89(m, 9H).

LC-MS: (m/z) 272.2 (MH⁺) t_(R) (minutes, method 3)=2.40 minutes

Example 9

7-(3-Fluorobenzyl)-3-(tetrahydro-2-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (200 mg,0.91 mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (189 mg, 1.37 mmol)and 1-(bromomethyl)-3-fluorobenzene (207 mg, 1.10 mmol). The reactionmixture was stirred at 60° C. for 16 hours. The mixture was filtered andthe filtrate was purified by preparative LC-MS to afford7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one190 mg (64%).

¹H NMR (DMSO-d₆, 400 Mhz): 57.68 (s, 1H), 7.54 (d, J=6.0 Hz, 1H),7.36-7.33 (m, 1H), 7.14-7.09 (m, 3H), 6.99 (d, J=6.0 Hz, 1H), 4.99 (s,2H), 3.91-3.88 (m, 2H), 3.48-3.42 (m, 2H), 3.30-3.29 (m, 1H), 1.81-1.73(m, 4H).

LC-MS: (m/z) 328.1 (MH⁺) t_(R) (minutes, method 1)=1.92 minutes

Example 10

7-(Cyclopentylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (400 mg,1.82 mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (503 mg, 3.64 mmol)and (bromomethyl)cyclopentane (445 mg, 2.73 mmol). The reaction mixturewas stirred at 600° C. for 16 hours. The mixture was filtered and thefiltrate was purified by preparative LC-MS to afford7-(cyclopentylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one290 mg (53%).

¹H NMR (DMSO-d₆, 400 Mhz): 57.62 (s, 1H), 7.49 (d, J=6.0 Hz, 1H), 6.90(d, J=6.0 Hz, 1H), 3.91-3.88 (m, 2H), 3.69 (d, J=7.6 Hz, 2H), 3.48-3.43(m, 2H), 3.42-3.31 (m, 1H), 2.27-2.24 (m, 1H), 1.78-1.73 (m, 4H),1.58-1.44 (m, 6H), 1.21-1.20 (m, 2H).

LC-MS: (m/z) 302.2 (MH⁺) t_(R) (minutes, method 3)=2.29 minutes

Example 11

7-(Cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (300 mg,1.37 mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (379 mg, 2.74 mmol)and (bromomethyl)cyclohexane (364 mg, 2.06 mmol). The reaction mixturewas stirred at 60° C. for 16 hours. The mixture was filtered and thefiltrate was purified by preparative LC-MS to yield7-(cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one240 mg (55%).

¹H NMR (DMSO-d₆, 400 Mhz): δ 7.62 (s, 1H), 7.47 (d, J=6.0 Hz, 1H), 6.84(d, J=6.2 Hz, 1H), 3.91-3.88 (m, 2H), 3.60 (d, J=7.2 Hz, 2H), 3.48-3.42(m, 2H), 3.30-3.29 (m, 1H), 1.78-1.52 (m, 10H), 1.10-1.06 (m, 3H),0.93-0.91 (m, 2H).

LC-MS: (m/z) 316.2 (MH⁺) t_(R) (minutes, method 3)=2.44 minutes.

Example 12

7-(Cycloheptylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (300 mg,1.37 mmol) in anhydrous DMF (4 mL) was added K₂CO₃ (568 mg, 4.11 mmol)and cycloheptylmethyl methanesulfonate (565 mg, 2.74 mmol). The reactionmixture was stirred at 95° C. for 16 hours. The mixture was filtered andthe filtrate was purified by preparative LC-MS to afford7-(cycloheptylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one140 mg (30%).

¹H NMR (DMSO-d₆, 400 MHz): δ7.62 (s, 1H), 6.48 (d, J=5.6 Hz, 1H), 6.87(d, J=6.0 Hz, 1H), 3.91-3.88 (m, 2H), 3.59 (d, J=7.6 Hz, 2H), 3.48-3.42(m, 2H), 3.31-3.26 (m, 1H), 1.90-1.73 (m, 5H), 1.57-1.43 (m, 10H),1.13-1.11 (m, 2H).

LC-MS: (m/z) 330.2 (MH⁺) t_(R) (minutes, method 3)=2.58 minutes

Example 13

7-(Cycloheptylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of 3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one (300 mg,1.71 mmol) in anhydrous DMF (4 mL) was added K₂CO₃ (709 mg, 5.1 mmol)and cycloheptylmethyl methanesulfonate (706 mg, 3.42 mmol). The reactionmixture was stirred at 95° C. for 16 hours. The mixture was filtered andthe filtrate was purified by preparative LC-MS to afford7-(cycloheptylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one 115mg (24%).

¹H NMR (DMSO-d₆, 400 MHz): δ7.55-7.52 (m, 2H), 6.89 (d, J=6.0 Hz, 1H),3.61 (d, J=7.6 Hz, 2H), 2.32-2.27 (m, 1H), 1.91 (brs, 1H), 1.91-1.02 (m,12H), 1.01-0.91 (m, 4H).

LC-MS: (m/z) 286.2 (MH⁺) t_(R) (minutes, method 3)=2.54 minutes.

Example 14

7-(4-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-4-chlorobenzene (132 mg, 0.643mmol) and Cs₂CO₃ (280 mg, 0.857 mmol) in DMF (2.0 mL) was stirred at 70°C. for 12 hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toafford7-(4-chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one53 mg (34%).

¹H NMR (CDCl₃, 400 MHz): δ7.93 (s, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.16 (d,J=8.4 Hz, 2H), 6.76 (s, 1H), 5.20 (s, 2H), 4.13 (d, J=10.8 Hz, 2H),3.62-3.56 (m, 2H), 3.12-3.05 (m, 1H), 2.18 (s, 3H), 2.16-2.09 (m, 2H),1.89 (d, J=13.2 Hz, 2H).

LC-MS: (m/z) 358.1 (MH⁺) t_(R) (minutes, method 3)=2.46 minutes

Example 15

6-Bromo-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-bromo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (100mg, 0.335 mmol), 1-(bromomethyl)-3-fluorobenzene (95 mg, 0.50 mmol) andK₂CO₃ (93 mg, 0.67 mmol) in DMF (2.0 mL) was stirred at 60° C. for 12hours. The reaction mixture was concentrated in vacuo. The residue waspurified by preparative LC-MS to give6-bromo-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one30 mg (22%).

¹H NMR (CDCl₃, 400 MHz): δ 7.95 (s, 1H), 7.34-7.27 (m, 1H), 7.18 (s,1H), 7.11 (d, J=7.6 Hz, 1H), 7.03-6.99 (m, 2H), 5.39 (s, 2H), 4.13 (d,J=12.0 Hz, 2H), 3.62-3.56 (m, 2H), 3.11-3.05 (m, 1H), 2.18-2.08 (m, 2H),1.88 (d, J=14.0 Hz, 2H).

LC-MS: (m/z) 408.0 (MH⁺) t_(R) (minutes, method 3)=2.65 minutes

Example 16

7-Benzyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), (bromomethyl)benzene (110 mg, 0.643 mmol) andK₂CO₃ (119 mg, 0.857 mmol) in DMF (1.0 mL) was stirred at 60° C. for 3hours. The mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by preparative LC-MS to yield7-benzyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one39 mg (28%).

¹H NMR (CDCl₃, 400 MHz): δ 7.93 (s, 1H), 7.35-7.29 (m, 3H), 7.21 (d,J=7.6 Hz, 2H), 6.75 (s, 1H), 5.25 (s, 2H), 4.13 (d, J=11.6 Hz, 2H),3.61-3.56 (m, 2H), 3.13-3.06 (m, 1H), 2.19 (s, 3H), 2.15-2.08 (m, 2H),1.89 (d, J=13.2 Hz, 2H).

LC-MS: (m/z) 324.2 (MH⁺) t_(R) (minutes, method 3)=2.25 minutes

Example 17

7-(2-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-2-fluorobenzene (122 mg, 0.643mmol) and Cs₂CO₃ (279 mg, 0.857 mmol) in DMF (2.0 mL) was stirred at 70°C. for 1 hour. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toafford7-(2-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one49 mg (33%).

1H NMR (CDCl₃, 400 MHz): δ 7.93 (s, 1H), 7.27-7.23 (m, 1H), 7.11-7.06(m, 3H), 6.77 (s, 1H), 5.28 (s, 2H), 4.13 (d, J=10.4 Hz, 2H), 3.62-3.56(m, 2H), 3.12-3.07 (m, 1H), 2.19 (s, 3H), 2.16-2.10 (m, 2H), 1.89 (d,J=12.0 Hz, 2H).

LC-MS: (m/z) 342.1 (MH⁺) t_(R) (minutes, method 3)=2.30 minutes

Example 18

7-(3-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-3-chlorobenzene (132 mg, 0.643mmol) and K₂CO₃ (119 mg, 0.857 mmol) in DMF (1.0 mL) was stirred at 65°C. for 12 hours. To the mixture was added Cs₂CO₃ (280 mg, 0.857 mmol)and the reaction was stirred at 80° C. for another 1 hour. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by preparative LC-MS to afford7-(3-chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one49 mg (32%).

¹H NMR (CDCl₃, 400 MHz): δ7.92 (s, 1H), 7.25-7.24 (m, 2H), 7.16 (s, 1H),7.10-7.07 (m, 1H), 6.75 (s, 1H), 5.19 (s, 2H), 4.11 (d, J=10.4 Hz, 2H),3.60-3.54 (m, 2H), 3.12-3.05 (m, 1H), 2.16 (s, 3H), 2.14-2.07 (m, 2H),1.87 (d, J=12.0 Hz, 2H).

LC-MS: (m/z) 358.1 (MH⁺) t_(R) (minutes, method 3)=2.44 minutes

Example 19

7-(2-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-2-chlorobenzene (132 mg, 0.643mmol) and Cs₂CO₃ (279 mg, 0.857 mmol) in DMF (2.0 mL) was stirred at 80°C. for 12 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toyield7-(2-chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one55 mg (36%).

¹H NMR (CDCl₃, 400 MHz): δ7.95 (s, 1H), 7.42-7.40 (m, 1H), 7.25-7.20 (m,2H), 6.93 (d, J=7.2 Hz, 1H), 6.80 (s, 1H), 5.32 (s, 2H), 4.14 (d, J=10.8Hz, 2H), 3.63-3.57 (m, 2H), 3.14-3.07 (m, 1H), 2.20-2.10 (m, 2H), 2.13(s, 3H), 1.91 (d, J=13.2 Hz, 2H).

LC-MS: (m/z) 358.1 (MH⁺) t_(R) (minutes, method 3)=2.46 minutes

Example 20

7-(3-Methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-3-methoxybenzene (129 mg, 0.643mmol) and Cs₂CO₃ (280 mg, 0.857 mmol) in DMF (1.0 mL) was stirred at 80°C. for 12 hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toyield7-(3-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one68 mg (45%).

¹H NMR (CDCl₃, 400 MHz): δ 7.92 (s, 1H), 7.27-7.23 (m, 1H), 6.82-6.77(m, 2H), 6.74 (s, 2H), 5.21 (s, 2H), 4.13 (d, J=10.8 Hz, 2H), 3.78 (s,3H), 3.62-3.56 (m, 2H), 3.12-3.08 (m, 1H), 2.19 (s, 3H), 2.19-2.10 (m,2H), 1.89 (d, J=13.2 Hz, 2H).

LC-MS: (m/z) 354.2 (MH⁺) t_(R) (minutes, method 3)=2.28 minutes

Example 21

6-Methyl-7-(2-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-2-methylbenzene (119 mg, 0.643mmol) and K₂CO₃ (119 mg, 0.857 mmol) in DMF (2.0 mL) was stirred at 60°C. for 12 hours. To the mixture was added additionally Cs₂CO₃ (280 mg,0.86 mmol) and the reaction stirred at 70° C. for another 13 hours. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by preparative LC-MS to afford6-methyl-7-(2-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one23 mg (16%).

¹H NMR (CDCl₃, 400 MHz): δ7.93 (s, 1H), 7.21-7.12 (m, 3H), 6.80 (s, 1H),6.78 (d, J=7.6 Hz, 1H), 5.18 (s, 2H), 4.15 (d, J=10.8 Hz, 2H), 3.63-3.57(m, 2H), 3.15-3.09 (m, 1H), 2.40 (s, 3H), 2.20-2.13 (m, 2H), 2.11 (s,3H), 1.92 (d, J=13.2 Hz, 2H).

LC-MS: (m/z) 338.2 (MH⁺) t_(R) (minutes, method 3)=2.37 minutes

Example 22

6-Methyl-7-(4-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-4-methylbenzene (119 mg, 0.643mmol) and Cs₂CO₃ (280 mg, 0.857 mmol) in DMF (2.0 mL) was stirred at 70°C. for 12 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toafford6-methyl-7-(4-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one68 mg (47%).

¹H NMR (CDCl₃, 400 MHz): δ7.92 (s, 1H), 7.14-7.09 (m, 4H), 6.74 (s, 1H),5.20 (s, 2H), 4.13 (d, J=10.4 Hz, 2H), 3.62-3.56 (m, 2H), 3.11-3.06 (m,1H), 2.32 (s, 3H), 2.19 (s, 3H), 2.19-2.08 (m, 2H), 1.88 (d, J=13.2 Hz,2H).

LC-MS: (m/z) 338.2 (MH⁺) t_(R) (minutes, method 3)=2.41 minutes.

Example 23

7-(4-Methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.43 mmol), 1-(bromomethyl)-4-methoxybenzene (129 mg, 0.643mmol) and Cs2CO3 (280 mg, 0.857 mmol) in DMF (2.0 mL) was stirred at 70°C. for 12 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toafford7-(4-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one60 mg (39%).

¹H NMR (CDCl₃, 400 MHz): δ7.93 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.86 (d,J=8.4 Hz, 2H), 6.73 (s, 1H), 5.17 (s, 2H), 4.13 (d, J=10.0 Hz, 2H), 3.79(s, 3H), 3.58 (t, J=12.0 Hz, 2H), 3.11-3.05 (m, 1H), 2.21 (s, 3H),2.18-2.08 (m, 2H), 1.88 (d, J=13.6 Hz, 2H).

LC-MS: (m/z) 354.2 (MH⁺) t_(R) (minutes, method 3)=2.26 minutes.

Example 24

7-(4-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-4-fluorobenzene (122 mg, 0.643mmol) and Cs₂CO₃ (279 mg, 0.857 mmol) in DMF (2.0 mL) was stirred at 70°C. for 12 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toyield7-(4-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one30 mg (21%).

¹H NMR (CDCl₃, 400 MHz): δ7.93 (s, 1H), 7.22-7.19 (m, 2H), 7.04-7.00 (m,2H), 6.75 (s, 1H), 5.20 (s, 2H), 4.13 (d, J=11.2 Hz, 2H), 3.62-3.60 (m,2H), 3.17-3.06 (m, 1H), 2.19 (s, 3H), 2.14-2.08 (m, 2H), 1.88 (d, J=13.6Hz, 2H).

LC-MS: (m/z) 342.1 (MH⁺) t_(R) (minutes, method 3)=2.30 minutes

Example 25

6-Methyl-7-(3-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 0.429 mmol), 1-(bromomethyl)-3-methylbenzene (119 mg, 0.643mmol) and Cs₂CO₃ (280 mg, 0.857 mmol) in DMF (1 mL) was stirred at 80°C. for 12 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by preparative LC-MS toafford6-methyl-7-(3-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one62 mg (43%).

¹H NMR (CDCl₃, 400 MHz): δ7.93 (s, 1H), 7.21 (t, J=7.2 Hz, 1H), 7.08 (d,J=7.6 Hz, 1H), 7.02-6.98 (m, 2H), 6.74 (s, 1H), 5.21 (s, 2H), 4.13 (d,J=10.8 Hz, 2H), 3.62-3.56 (m, 2H), 3.12-3.07 (m, 1H), 2.33 (s, 3H), 2.19(s, 3H), 2.19-2.09 (m, 2H), 1.89 (d, J=13.2 Hz, 2H).

LC-MS: (m/z) 338.1 (MH⁺) t_(R) (minutes, method 3)=2.40 minutes.

Example 26

7-(3-fluorobenzyl)-6-methyl-3-(4-methyethydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(150 mg, 0.98 mmol) and 4-methyltetrahydro-2H-pyran-4-carboxylic acid(212 mg, 1.5 mmol) in DCM (6 mL) was added HATU (670 mg, 1.8 mmol) andEt₃N (198 mg, 1.96 mmol). The mixture was stirred at 20-25° C. for 1hour. The mixture was diluted with DCM (50 mL), washed with water (30mL) and brine (30 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=3:1) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-4-methyltetrahydro-2H-pyran-4-carboxamide(250 mg, 91% yield).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-4-methyltetrahydro-2H-pyran-4-carboxamide(300 mg, 1.07 mmol) in dioxane (5 mL) was added POCl₃ (660 mg, 4.3mmol). The solution was stirred at 80-90° C. for 3 hours. The mixturewas concentrated in vacuo, diluted with DCM (50 mL) and slowly addedinto water (30 mL). The organic layer was washed with brine (20 mL) anddried over Na₂SO₄, concentrated in vacuo to give8-methoxy-6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine(250 mg, 89% yield).

Step 3: To a solution of8-methoxy-6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine(200 mg, 0.77 mmol) in dioxane (10 mL) was added 2M HCl(aq) (10 mL). Thesolution was stirred at 80-90° C. for 1 hour. The mixture was cooled andadded saturated aqueous NaHCO₃ (100 mL), extracted with DCM (100 mL×2).The organic layer was washed with brine (50 mL), dried over Na₂SO₄ andconcentrated in vacuo to give6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(160 mg, 68% yield).

LC-MS: t_(R)=0.89 min (method 10), m/z=248.3 [M+H]⁺.

Step 4: To a solution of6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 0.81 mmol) and 1-(bromomethyl)-3-fluorobenzene (183 mg, 0.97mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (168 mg, 1.21 mmol). Themixture was stirred at 60-70° C. for 16 h. The mixture was cooled anddiluted with water (20 mL), extracted with EtOAc (30 mL×2). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=1:2) to give7-(3-fluorobenzyl)-6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(90 mg, 31% yield) as a off-white solid.

¹H NMR (CDC₃ 400 MHz): δ 7.94 (s, 1H), 7.33-7.28 (m, 1H), 7.02-6.91 (m,4H), 5.22 (s, 2H), 3.85-3.80 (m, 2H), 3.73-3.67 (m, 2H), 2.45-2.41 (m,2H), 2.17 (s, 3H), 1.86-1.79 (m, 2H), 1.49 (s, 3H).

LC-MS: t_(R)=2.46 min (method 3), m/z=356.2 [M+H]⁺.

Example 27

4-(7-(3-fluorobenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(100 mg, 0.65 mmol) and 4-cyanotetrahydro-2H-pyran-4-carboxylic acid(152 mg, 0.98 mmol) in DCM (6 mL) was added HATU (447 mg, 1.18 mmol) andEt₃N (132 mg, 1.31 mmol). The mixture was stirred at 20-25° C. for 1hour. The mixture was diluted with DCM (30 ml), washed with water (20mL) and brine (20 mL). The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=1:1) to give4-cyano-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide(100 mg, 53% yield).

LC-MS: t_(R)=0.61 min (method 2), m/z=290.9 [M+H]⁺.

Step 2: To a solution of4-cyano-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide(100 mg, 0.34 mmol) in dioxane (5 mL) was added POCl₃ (330 mg, 2.15mmol). The solution was stirred at 80-90° C. for 2 h. The mixture wascooled and slowly added into water (50 mL), extracted with EtOAc (30mL×2). The organic layer was washed with brine (20 mL), dried overNa₂SO₄ and concentrated in vacuo to give4-(8-methoxy-6-methylimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(80 mg, 85% yield).

Step 3: To a solution of4-(8-methoxy-6-methylimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(80 mg, 0.29 mmol) in dioxane (4 mL) was added 2M HCl(aq) (2 mL). Thesolution was stirred at 80-90° C. for 2 h. The mixture was concentratedin vacuo and added saturated aqueous NaHCO₃ (50 mL). The mixture wasextracted with DCM (50 mL×2). The organic layer was washed with brine(20 mL) and concentrated in vacuo to give4-(6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(70 mg, 92% yield) as a off-white solid.

LC-MS: t_(R)=0.98 min (method 10), m/z=259.2 [M+H]⁺.

Step 4: To a solution of4-(6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(70 mg, 0.27 mmol) in anhydrous DMF (5 mL) was added1-(bromomethyl)-3-fluoro-benzene (77 mg, 0.41 mmol) and K₂CO₃ (75 mg,0.54 mmol). The mixture was stirred at 70-80° C. for 2 h. The mixturewas cooled and filtered. The filtrate was purified by preparative LC-MSto give4-(7-(3-fluorobenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile(65 mg, 65% yield).

¹H NMR (CDCl₃400 MHz): δ 7.97 (s, 1H), 7.34-7.31 (m, 1H), 7.16 (s, 1H),7.02-6.92 (m, 3H), 5.26 (s, 2H), 4.13-4.10 (m, 2H), 3.97-3.91 (m, 2H),2.50-2.43 (m, 2H), 2.35-2.32 (m, 2H), 2.24 (s, 3H).

LC-MS: t_(R)=2.69 min (method 3), m/z=367.1 [M+H]⁺.

Example 28

7-(3-fluorobenzyl)-3-(4-methoxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of 3-bromo-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(500 mg, 2.2 mmol) and 1-(bromomethyl)-3-fluorobenzene (497 mg, 2.6mmol) in DMF (5 mL) was added K₂CO₃ (605 mg, 4.4 mmol). The mixture wasstirred at 60° C. for 12 hours. The mixture was diluted with water (20mL) and extracted with EtOAc (10 mL×3). The combine organic layer waswashed with water (10 mL×2); dried over Na2SO4 and evaporated undervacuum to give3-bromo-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (420mg, 57% yield).

Step 2: To a solution of3-bromo-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (200mg, 0.6 mmol) in THF (10 mL) was added n-BuLi (0.31 mL, 0.77 mmol) at−78° C. The mixture was stirred at −78° C. for 30 minutes.tetrahydro-4H-pyran-4-one (77 mg, 0.77 mmol) was added at −78° C. Themixture was stirred at −78° C. for 1 hour. The mixture was quenched withsaturated aqueous NH₄Cl (0.5 mL) and evaporated under vacuum. Theresidue was dissolved in DCM (20 mL) and washed with water (10 mL). Theorganic layer was dried over Na₂SO₄ and evaporated. The residue waswashed with EtOAc (3 mL) and filtered. The filter cake was dried undervacuum to give7-(3-fluorobenzyl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 47% yield).

Step 3: To a solution of7-(3-fluorobenzyl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(80 mg, 0.22 mmol) in THF (5 mL) was added NaH (60% in mineral oil, 13.4mg, 0.36 mmol) at 0° C. The mixture was stirred at 20° C. for 30minutes. Mel (64 mg, 0.45 mmol) was added at 0° C. The mixture wasstirred at 20° C. for 11.5 hours. The mixture was quenched withsaturated aqueous NH₄Cl (0.5 mL) and evaporated under vacuum. Theresidue was dissolved in DCM (10 mL) and washed with water (4 mL). Theorganic layer was dried over Na₂SO₄ and evaporated. The residue waspurified by preparative TLC (EtOAc) to give7-(3-fluorobenzyl)-3-(4-methoxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(25 mg, 30% yield).

¹H NMR (CDCl₃, 400 MHz): δ7.93 (s, 1H), 7.36 (s, 1H), 7.31 (dd, J=8.0Hz, J=14.0 Hz, 1H), 7.03-6.92 (m, 3H), 5.23 (s, 2H), 3.91-3.80 (m, 4H),3.07 (s, 3H), 2.38-2.31 (m, 2H), 2.17 (s, 3H), 2.14-2.10 (m, 2H).

LC-MS: t_(R)=2.73 min (method 3), m/z=372.1 [M+H]⁺.

Example 29

7-(3-fluorobenzyl)-3-(4-fluorotetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of3-bromo-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (100mg, 0.3 mmol) in dry THF (5 mL) was added n-BuLi (2.5 M, 0.15 mL) (2.5 Min n-hexane) dropwise. The mixture was stirred at −78° C. for 0.5 hours.Then tetrahydro-4H-pyran-4-one (45 mg, 0.45 mmol) was added to themixture. The mixture was stirred at −78° C. for 2 hours. The mixture wasquenched with saturated aqueous NH₄Cl (2 mL). The mixture was extractedwith DCM (20 mL×2). The combined organic layer was washed with H₂O (10mL), brine (10 mL), dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (1%˜10% MeOH in DCM) to give7-(3-fluorobenzyl)-3-(4-hydroxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 38% yield).

LC-MS: t_(R)=0.671 min (method 2), m/z=358.1 [M+H]⁺.

Step 2: To a solution of7-(3-fluorobenzyl)-3-(4-fluorotetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 111.9 μmol) in dry DCM (4 mL) was added DAST (diethylaminosulfurtrifluoride) (28 mg, 170 μmol) at 0° C. The mixture was stirred at 0° C.for 2 hours. Water (10 mL) was added to the mixture. The mixture wasextracted with DCM (20 mL×2). The combined organic layer was washed withH₂O (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by preparative TLC(DCM/MeOH=10/1) to give7-(3-fluorobenzyl)-3-(4-fluorotetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(12.83 mg, 32% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.93 (s, 1H), 7.34-7.28 (m, 1H), 7.21 (s, 1H),7.01-6.98 (m, 2H), 6.92 (d, J=9.6 Hz, 1H), 5.24 (s, 2H), 4.00-3.89 (m,4H), 2.57-2.42 (m, 2H), 2.23-2.18 (m, 5H).

LC-MS: t_(R)=2.753 min (method 3), m/z=360.1 [M+H]⁺.

Example 30

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 and 2

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(200 mg, 1.31 mmol) in DCM (8 mL) was addedtetrahydro-2H-pyran-2-carboxylic acid (255 mg, 1.96 mmol) and HATU (894mg, 2.35 mmol), Et₃N (264 mg, 2.61 mmol). The solution was stirred at20-25° C. for 1 hour. The mixture was diluted with water (30 mL),extracted with DCM (40 mL×2). The organic layer was washed with brine(20 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=1:1) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-2-carboxamide(250 mg, 72% yield). LC-MS: t_(R)=0.70 min (method 2), m/z=266.2 [M+H]⁺.

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-2-carboxamide(250 mg, 0.94 mmol) in dioxane (8 mL) was added POCl₃ (480 mg, 3.13mmol). The solution was stirred at 90° C. for 2 h. The mixture wascooled and concentrated in vacuo. The residue was diluted with DCM (50mL), washed with saturated aqueous NaHCO₃ (aq) (50 mL) and brine (50mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuoto give8-methoxy-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazine(200 mg, 86% yield).

Step 3: To a solution of8-methoxy-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazine(270 mg, 1.09 mmol) in dioxane (8 mL) was added 2M HCl(aq) (4 mL). Thesolution was stirred at 90° C. for 1 hour. The mixture was concentratedin vacuo and added saturated aqueous NaHCO₃ (50 mL). The mixture wasextracted with DCM (50 mL×2). The organic layer was washed with brine(50 mL) and concentrated in vacuo to give6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 79% yield).

Step 4: To a solution of6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 0.86 mmol) in anhydrous DMF (10 mL) was added K₂C₀₃ (237 mg,1.71 mmol) and 1-(bromomethyl)-3-fluorobenzene (243 mg, 1.29 mmol). Themixture was stirred at 80° C. for 24 h. The mixture was cooled anddiluted with water (100 mL), extracted with EtOAc (50 mL×3). The organiclayer was washed with brine (50 mL), dried over Na₂SO₄ and concentratedin vacuo to give7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one(130 mg, 44% yield).

Step 5:7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one(130 mg, 380.8 μmol) was purified by SFC.7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 (35 mg, 27% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.91 (s, 1H), 7.32-7.28 (m, 1H), 7.19 (s, 1H),6.98-6.94 (m, 2H), 6.89 (d, J=9.6 Hz, 1H), 5.23 (s, 2H), 4.76 (t, J=6.4Hz, 1H), 4.06 (d, J=10.8 Hz, 1H), 3.67 (t, J=10.8 Hz, 1H), 2.23 (s, 3H),2.17-2.05 (m, 3H), 1.74-1.68 (m, 3H).

LC-MS: t_(R)=2.33 min (method 3), m/z=342.1 [M+H]⁺. SFC: t_(R)=5.478min, ee %=99.90%. [α]_(D) ²⁰+16.00 (c=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (33 mg, yield: 35%) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.32-7.28 (m, 1H), 7.19 (s, 1H),6.98-6.94 (m, 2H), 6.89 (d, J=9.2 Hz, 1H), 5.23 (s, 2H), 4.77 (t, J=6.8Hz, 1H), 4.06 (d, J=10.8 Hz, 1H), 3.67 (t, J=10.8 Hz, 1H), 2.17 (s, 3H),2.12-2.02 (m, 3H), 1.74-1.68 (m, 3H).

LC-MS: t_(R)=2.33 min (method 3), m/z=342.1 [M+H]⁺. SFC: t_(R)=5.789min, ee %=98.92%. [α]_(D) ²⁰−23.33 (c=0.10, CHCl₃).

Example 31

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7)-one,stereosiomer 1 and 2

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(200 mg, 1.3 mmol) in dry DCM (10 mL) was addedtetrahydrofuran-3-carboxylic acid (228 mg, 2.0 mmol), Et₃N (265 mg, 2.6mmol) and HATU (747 mg, 2.0 mmol). The mixture was stirred at 15° C. for16 hours. Water (10 mL) was added to the mixture. The organic layer waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give the crude product. The crude product was purified by flashchromatography on silica gel (10%˜100% ethyl acetate in petroleum ether)to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydrofuran-3-carboxamide(200 mg, 61% yield).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydrofuran-3-carboxamide(300 mg, 1.19 mmol) in dioxane (5 mL) was added POCl₃ (366 mg, 2.39mmol). The mixture was heated at 90° C. for 2 hours. The mixture wascooled to 15° C. and adjusted to pH=8 by saturated aqueous NaHCO₃. Theaqueous layer was extracted with DCM (20 mL×2). The combined organiclayer was washed with H₂O (20 ml), brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give8-methoxy-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine (300mg).

Step 3: To a solution of8-methoxy-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine (300mg, 1.29 mmol) in dioxane (5 mL) was added 2 N HCl (2 mL). The mixturewas heated at 90° C. for 1 hour. The mixture was cooled to 15° C. andextracted with DCM (20 mL×2).

The combined organic layer was washed with H₂O (20 mL), brine (20 mL),dried over Na₂SO₄, filtered and concentrated to give6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (210mg, 74% yield).

Step 4: To a solution of6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one (200mg, 912.24 μmol) in dry DMF (5 mL) was added1-(bromomethyl)-3-fluorobenzene (259 mg, 1.37 mmol) and K₂CO₃ (252 mg,1.82 mmol). The mixture was stirred at 60° C. for 16 hours. The mixturewas concentrated and the residue was dissolved in DCM (20 mL) and H₂O(10 mL). The aqueous layer was extracted with DCM (20 mL×2). Thecombined organic layer was washed with H₂O (20 mL), brine (20 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel(10%˜100% ethyl acetate in petroleum ether) to give7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 13% yield).

Step 5:7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 122.2 μmol) was purified by SFC to give7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 (16.43 mg, 41% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.90 (s, 1H), 7.31-7.28 (m, 1H), 6.98-6.93 (m,2H), 6.89 (d, J=9.2 Hz, 1H), 6.79 (s, 1H), 5.21 (s, 2H), 4.19-4.17 (m,1H), 4.12-4.09 (m, 1H), 4.05-3.95 (m, 2H), 3.66-3.62 (m, 1H), 2.40 (q,J=7.2 Hz, 2H), 2.16 (s, 3H).

LC-MS: t_(R)=1.964 min (method 3), m/z=328.0 [M+H]⁺. SFC: t_(R)=4.503min, ee %=99.8%; [α]_(D) ²⁰+14.7 (c=0.10, DCM).

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (15.58 mg, 38% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.90 (s, 1H), 7.29-7.27 (m, 1H), 6.98-6.92 (m,2H), 6.89 (d, J=9.6 Hz, 1H), 6.79 (s, 1H), 5.21 (s, 2H), 4.19 (t, J=8.4Hz, 1H), 4.11-4.09 (m, 1H), 4.05-4.03 (m, 1H), 3.97-3.95 (m, 1H),3.66-3.62 (m, 1H), 2.38 (q, J=7.6 Hz, 2H), 2.16 (s, 3H).

LC-MS: t_(R)=1.957 min (method 3), m/z=328.0 [M+H]⁺. SFC: t_(R)=4.779min, ee %=96%; [α]_(D) ²⁰−14.0 (c=0.10, DCM).

Example 32

7-(3-fluorobenzyl)-6-methy-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 and 2

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(200 mg, 1.3 mmol) in DCM (6 mL) was added3-methyltetrahydrofuran-3-carboxylic acid (255 mg, 1.9 mmol) and HATU(894 mg, 2.4 mmol), Et₃N (264 mg, 2.6 mmol). The solution was stirred at20-25° C. for 1 hour. Water (40 ml) was added, the mixture was extractedwith DCM (40 mL×2). The organic layer was washed with brine (30 mL),dried over Na₂SO₄ and concentrated in vacuo. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=1:1) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyltetrahydrofuran-3-carboxamide(300 mg, 67% yield, 78% purity).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyltetrahydrofuran-3-carboxamide(400 mg, 1.5 mmol) in dioxane (6 mL) was added POCl₃ (880 mg, 5.7 mmol).The solution was stirred at 80-90° C. for 2 h. The mixture was cooledand concentrated in vacuo. The residue was diluted with DCM (50 mL),washed with saturated aqueous NaHCO₃ (50 mL) and brine (50 mL). Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to give8-methoxy-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine(350 mg, 94% yield).

Step 3: To a solution of8-methoxy-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine(300 mg, 1.2 mmol) in dioxane (8 mL) was added 2M HCl(aq) (4 mL). Thesolution was stirred at 80-90° C. for 1 hour. The mixture wasconcentrated in vacuo and added saturated aqueous NaHCO₃ (50 mL). Themixture was extracted with DCM (50 mL×2). The organic layer was washedwith brine (20 mL) and concentrated in vacuo to give6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(260 mg, 92% yield).

Step 4: To a solution of6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(260 mg, 1.1 mmol) in anhydrous DMF (10 mL) was added K₂CO₃ (308 mg, 2.2mmol) and 1-(bromomethyl)-3-fluorobenzene (316 mg, 1.7 mmol). Themixture was stirred at 70-80° C. for 2 h. The mixture was cooled anddiluted with water (50 mL), extracted with EtOAc (50 mL×2). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄ and concentratedin vacuo to give7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(160 mg, 42% yield).

Step 5:7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(160 mg, 0.47 mmol) was separated by SFC to give7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 (37 mg, 23% yield) as a off-white solid. ¹H NMR (CDCl₃400MHz): δ 7.88 (s, 1H), 7.32-7.26 (m, 1H), 6.94-6.82 (m, 4H), 5.21 (s,2H), 4.33 (d, J=8.8 Hz, 1H), 4.07-4.04 (m, 1H), 4.00-3.98 (m, 1H), 3.87(d, J=8.8 Hz, 1H), 2.62-2.57 (m, 1H), 2.16 (s, 3H), 2.14-2.09 (m, 1H),1.60 (s, 3H). LC-MS: t_(R)=2.47 min (method 3), m/z=342.1 [M+H]⁺. SFC:t_(R)=4.91 min, ee %>99%. [α]_(D) ²⁰=+5.0 (c=0.10, MeOH).

7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (44 mg, 27% yield) as a off-white solid.

¹H NMR (CDCl₃400 MHz): δ 7.82 (s, 1H), 7.24-7.20 (m, 1H), 6.94-6.82 (m,4H), 5.15 (s, 2H), 4.27 (d, J=8.8 Hz, 1H), 4.01-3.99 (m, 1H), 3.96-3.92(m, 1H), 3.81 (d, J=8.8 Hz, 1H), 2.57-2.51 (m, 1H), 2.10 (s, 3H),2.09-2.04 (m, 1H), 1.54 (s, 3H).

LC-MS: t_(R)=2.47 min (method 3), m/z=342.1 [M+H]⁺.

SFC: t_(R)=5.33 min, ee %>99%. [α]_(D) ²⁰=−3.0 (c=0.10, MeOH).

Example 33

7-(3-fluorobenzyl)-6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of 1-methylcyclopropane-1-carboxylic acid (500 mg,4.99 mmol) in DCM (2 mL) was added (COCl)₂ (3.17 g, 24.95 mmol). Thesolution was stirred at 40° C. for 2 h. The reaction mixture wasconcentrated in vacuo to give 1-methylcyclopropane-1-carbonyl chloride(500 mg, 85% yield).

Step 2: A solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine (100mg, 0.65 mmol) in anhydrous DCM (3 mL) was cooled to 0° C. Then asolution of 1-methylcyclopropane-1-carbonyl chloride (100 mg, 0.85 mmol)in anhydous DCM (2 mL) was added dropwise and stirred at 0° C. for 15min. The mixture was diluted with DCM (20 mL), washed with saturatedaqueous NaHCO₃ (20 mL), brine (20 mL) and dried over Na₂SO₄. The organiclayer was concentrated in vacuo to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-1-methylcyclopropane-1-carboxamide(120 mg, 78% yield).

LC-MS: t_(R)=0.66 min (method 2), m/z=236.1 [M+H]⁺.

Step 3: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-1-methylcyclopropane-1-carboxamide(120 mg, 0.51 mmol) in dioxane (5 mL) was added POCl₃ (590 mg, 3.85mmol). The solution was stirred at 80-90° C. for 2 h. The mixture wascooled and slowly added into water (50 mL), extracted with EtOAc (30mL×2). The organic layer was washed with brine (20 mL), dried overNa₂SO₄ and concentrated in vacuo to give8-methoxy-6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazine (80 mg,72% yield).

Step 4: To a solution of8-methoxy-6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazine (80 mg,0.37 mmol) in dioxane (5 mL) was added 2M HCl (aq) (2 mL). The solutionwas stirred at 80-90° C. for 1 hour. The mixture was concentrated invacuo and added saturated aqueous NaHCO₃ (50 mL). The mixture wasextracted with DCM (50 mL×2). The organic layer was washed with brine(20 mL) and concentrated in vacuo to give6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one (70 mg,94% yield).

Step 5: To a solution of6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one (70 mg,0.34 mmol) in anhydrous DMF (4 mL) was added1-(bromomethyl)-3-fluoro-benzene (98 mg, 0.52 mmol) and K₂CO₃ (95 mg,0.69 mmol). The mixture was stirred at 70-80° C. for 1 hour. The mixturewas cooled and filtered. The filtrate was purified by preparative LC-MSto give7-(3-fluorobenzyl)-6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one(35 mg, 32% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.84 (s, 1H), 7.33-7.39 (m, 1H), 7.01-6.89 (m,4H), 5.23 (s, 2H), 2.20 (s, 3H), 1.60 (s, 3H), 1.11-1.09 (m, 2H),0.88-0.85 (m, 2H).

LC-MS: t_(R)=2.34 min (method 3), m/z=312.1 [M+H]⁺.

Example 34

3-(2,2-diflurorocyclopropyl)-7(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(100 mg, 0.65 mmol) in DCM (5 mL) was added2,2-difluorocyclopropane-1-carboxylic acid (120 mg, 0.98 mmol) and HATU(447 mg, 1.18 mmol), Et₃N (132 mg, 1.31 mmol). The solution was stirredat 20-25° C. for 1 hour. The mixture was diluted with water (20 mL),extracted with DCM (30 mL×2). The organic layer was washed with brine(20 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=1:1) to give2,2-difluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide(200 mg, 89% yield, 75% purity).

Step 2. To a solution of2,2-difluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide(200 mg, 0.58 mmol, 75% purity) in dioxane (5 mL) was added POCl₃ (1.12g, 7.3 mmol). The solution was stirred at 90° C. for 2 h. The mixturewas cooled and concentrated in vacuo. The residue was diluted with DCM(50 mL), washed with saturated aqueous NaHCO₃(aq) (50 mL) and brine (50mL). The organic layer was dried over Na₂SO₄ and concentrated in vacuoto give3-(2,2-difluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine(120 mg, 86% yield).

Step 3: To a solution of3-(2,2-difluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine(120 mg, 0.50 mmol) in dioxane (5 mL) was added 2M HCl(aq) (3 mL). Thesolution was stirred at 80° C. for 1 hour. The mixture was concentratedin vacuo and added saturated aqueous NaHCO₃ (50 mL). The mixture wasextracted with DCM (50 mL×2). The organic layer was washed with brine(20 mL) and concentrated in vacuo to give3-(2,2-difluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (100mg, 89% yield).

LC-MS: t_(R)=0.94 min (method 10), m/z=226.2 [M+H]⁺.

Step 4: To a solution of3-(2,2-difluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (100mg, 0.44 mmol) in anhydrous DMF (5 mL) was added K₂CO₃ (123 mg, 0.89mmol) and 1-(bromomethyl)-3-fluorobenzene (126 mg, 0.67 mmol). Themixture was stirred at 80° C. for 2 h. The mixture was cooled andfiltered. The filtrate was purified by preparative LC-MS to give3-(2,2-difluorocyclopropyl)-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 27% yield) as a white solid.

¹H NMR (CDC₃ 400 MHz): δ 57.90 (s, 1H), 7.30-7.28 (m, 1H), 6.98-6.84 (m,4H), 5.28-5.16 (m, 2H), 2.80-2.73 (m, 1H), 2.38-2.37 (m, 1H), 2.19 (s,3H), 2.05-2.04 (m, 1H).

LC-MS: t_(R)=2.67 min (method 3), m/z=334.1 [M+H]⁺.

Example 35

7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1, 2, 3 and 4

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(100 mg, 652.8 μmol) and 2-methylcyclopropane-1-carboxylic acid (98 mg,979.2 μmol) in DCM (5 mL) was added HATU (446.8 mg, 1.2 mmol) andtriethylamine (132.1 mg, 1.3 mmol). The mixture was stirred at 24° C.for 16 h. The mixture was diluted with DCM (20 mL) and washed with water(15 mL). The aqueous layer was extracted with DCM (2*30 mL). Thecombined organic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by preparative TLC(ethyl acetate) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methylcyclopropane-1-carboxamide(150 mg, 95% yield).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methylcyclopropane-1-carboxamide(150 mg, 636 μmol) in dioxane (5 mL) was added POCl₃ (400 mg, 2.6 mmol).The mixture was stirred at 90° C. for 2 h. The mixture was cooled downto 25° C., neutralized with saturated aqueousNaHCO₃ and extracted withethyl acetate (3×30 mL). The combined organic layer was washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude 8-methoxy-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazine(130 mg, 94% yield). This crude product was used directly for the nextstep.

Step 3: A solution of8-methoxy-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazine (120mg, 552.3 μmol) in dioxane (5 mL) and HCl (2 M, 2 mL) was stirred at 80°C. for 1 hour. The mixture was cooled to 25° C., neutralized withsaturated aqueous NaHCO₃ and extracted with ethyl acetate (3×20 mL). Thecombined organic layer was washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one (100 mg,89% yield). This crude product was used directly for the next step.

Step 4: To a solution of6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one (100 mg,492.0 μmol) and 1-(bromomethyl)-3-fluorobenzene (139.5 mg, 738.0 μmol)in DMF (5 mL) was added K₂CO₃ (136 mg, 984 μmol). The mixture wasstirred at 60-70° C. for 16 h. The mixture was cooled to 25° C., dilutedwith water (15 mL), extracted with ethyl acetate (3×30 mL). The combinedorganic layer was washed with brine (30 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica gel (eluent of 0%˜50% ethyl acetate in petroleum ether) to give7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one(80 mg, 52% yield).

Step 5:7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 321.2 μmol) was purified by SFC.

7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 (35 mg, 27% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.83 (s, 1H), 7.33-7.29 (m, 1H), 7.00-6.94 (m,2H), 6.91-6.89 (m, 2H), 5.23 (s, 2H), 2.19 (s, 3H), 1.59-1.55 (m, 1H),1.54-1.50 (m, 1H), 1.35-1.30 (m, 1H), 1.27 (d, J=6.0 Hz, 3H), 0.89-0.88(m, 1H).

LC-MS: t_(R)=2.03 min (method 3), m/z=312.1 [M+H]⁺. SFC: t_(R)=4.466min, ee %>99%. [α]_(D) ²⁰+29.3 (c=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (26 mg, 26% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.84 (s, 1H), 7.32-7.29 (m, 1H), 7.00-6.96 (m,2H), 6.90-6.89 (m, 2H), 5.23 (s, 2H), 2.19 (s, 3H), 1.62-1.60 (m, 1H),1.55-1.53 (m, 1H), 1.36-1.34 (m, 1H), 1.27 (d, J=5.6 Hz, 3H), 0.91-0.89(m, 1H).

LC-MS: t_(R)=2.02 min (method 3), m/z=312.1 [M+H]⁺. SFC: t_(R)=5.227min, ee %>99%. [α]D₂₀−15.0 (c=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 3 (8.0 mg, 8% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.89 (s, 1H), 7.33-7.30 (m, 1H), 7.01-6.91 (m,4H), 5.29 (d, J=16.0 Hz, 1H), 5.17 (d, J=16.0 Hz, 1H), 2.19 (s, 3H),2.01-1.97 (m, 1H), 1.39-1.27 (m, 1H), 1.23-1.20 (m, 2H), 0.91 (d, J=6.0Hz, 3H).

LC-MS: t_(R)=1.98 min (method 3), m/z=312.1 [M+H]⁺. SFC: t_(R)=6.995min, ee %>99%. [α]_(D) ²⁰+37.0 (c=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 4 (9.0 mg, 9% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.86 (s, 1H), 7.29-7.26 (m, 1H), 6.99-6.88 (m,4H), 5.27 (d, J=16.0 Hz, 1H), 5.15 (d, J=16.0 Hz, 1H), 2.17 (s, 3H),1.97-1.95 (m, 1H), 1.58-1.53 (m, 1H), 1.23-1.20 (m, 2H), 0.91 (d, J=6.0Hz, 3H).

LC-MS: t_(R)=1.98 min (method 3), m/z=312.1 [M+H]⁺. SFC: t_(R)=8.704min, ee %>99%. [α]_(D) ²⁰−66.7 (c=0.10, CHCl₃).

Example 36

7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1, 2, 3 and 4

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(300 mg, 2.0 mmol), 2-methyltetrahydrofuran-3-carboxylic acid (382 mg,2.9 mmol) in DCM (10 mL) was added HATU (1.3 g, 3.5 mmol) andtriethylamine (396 mg, 3.9 mmol). The mixture was stirred at 24° C. for16 h. The mixture was diluted with DCM (30 mL) and washed with water (20mL). The aqueous layer was extracted with DCM (2×30 mL). The combinedorganic layer was washed with brine (30 mL), dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography onsilica gel (0%˜70% ethyl acetate in petroleum ether) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyltetrahydrofuran-3-carboxamide(350 mg, 62% yield).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyltetrahydrofuran-3-carboxamide(350 mg, 1.3 mmol) in dioxane (5 mL) was added POCl₃ (720 mg, 4.7 mmol).The mixture was stirred at 90° C. for 2 h. The mixture was cooled to 25°C., neutralized with saturated aq.NaHCO₃ and extracted with ethylacetate (2×30 mL). The combined organic layer was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to give crude8-methoxy-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine(320 mg). The crude was used directly for the next step.

Step 3: A solution of8-methoxy-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine(320 mg, 1.3 mmol) in dioxane (5 mL) and HCl (2 M, 2 mL) was stirred at80° C.-90° C. for 21.5 hours. The mixture was cooled down to 25° C.,neutralized with saturated aq.NaHCO₃, extracted with DCM (3×30 mL). Thecombined organic layer was washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give crude6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(300 mg). The crude product was used directly for the next step.

Step 4: To a solution of6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(250 mg, 1.1 mmol) in DMF (8 mL) was added1-(bromomethyl)-3-fluorobenzene (304 mg, 1.6 mmol) and K₂CO₃ (296 mg,2.1 mmol). The mixture was stirred at 60-70° C. for 16 h. The mixturewas cooled down to 25° C. and diluted with water (15 mL), extracted withethyl acetate (3×30 mL). The combined organic layer was washed withbrine (30 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography on silica gel (eluent of 0%˜30%ethyl acetate in petroleum ether) to give7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(170 mg, 47% yield).

Step 5:7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(220 mg, 644 μmol) was purified by SFC.

7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 (20 mg, 9% yield).

¹H NMR (CDCl₃ 400 MHz400 MHz): δ 7.95 (s, 1H), 7.34-7.28 (m, 1H),7.01-6.89 (m, 3H), 6.79 (s, 1H), 5.23 (s, 2H), 4.35-4.30 (m, 1H),4.13-4.07 (m, 2H), 3.12-3.06 (m, 1H), 2.50-2.37 (m, 2H), 2.19 (s, 3H),1.35 (d, J=6.0 Hz, 3H.

LC-MS: t_(R)=2.12 min (method 3), m/z=342.1 [M+H]⁺.

SFC: t_(R)=4.812 min, ee %>99%. [α]D₂₀−24.3 (c=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (10 mg, 5% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.93 (s, 1H), 7.31-7.26 (m, 1H), 6.99-6.87 (m,3H), 6.76 (s, 1H), 5.21 (s, 2H), 4.32-4.27 (m, 1H), 4.10-4.04 (m, 2H),3.10-3.03 (m, 1H), 2.48-2.35 (m, 2H), 2.17 (s, 3H), 1.33 (d, J=6.4 Hz,3H).

LC-MS: t_(R)=2.07 min (method 3), m/z=342.1 [M+H]⁺.

SFC: t_(R)=5.088 min, ee %=97.9%. [α]_(D) ²⁰+10.3 (c=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 3 (38.0 mg, 17% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.95 (s, 1H), 7.31-7.29 (m, 1H), 7.01-6.89 (m,3H), 6.83 (s, 1H), 5.29 (d, J=16.4 Hz, 1H), 5.17 (d, J=16.4 Hz, 1H),4.35-4.28 (m, 2H), 3.91-3.87 (m, 1H), 3.71-3.67 (m, 1H), 2.72-2.67 (m,1H), 2.44-2.40 (m, 1H), 2.18 (s, 3H), 0.90 (d, J=6.4 Hz, 3H).

LC-MS: t_(R)=2.02 min (method 3), m/z=342.1 [M+H]⁺. SFC: t_(R)=5.516min, ee %>99%. [α]D²⁰+46.3 (C=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 4 (30.0 mg, 14% yield). ¹H NMR (CDCl₃ 400 MHz): δ 7.95 (s,1H), 7.33-7.30 (m, 1H), 7.01-6.90 (m, 3H), 6.83 (s, 1H), 5.29 (d, J=16.4Hz, 1H), 5.17 (d, J=16.4 Hz, 1H), 4.37-4.28 (m, 2H), 3.91-3.87 (m, 1H),3.71-3.69 (m, 1H), 2.72-2.68 (m, 1H), 2.45-2.40 (m, 1H), 2.18 (s, 3H),0.90 (d, J=6.8 Hz, 3H).

LC-MS: t_(R)=1.98 min (method 3), m/z=342.1 [M+H]⁺. SFC: t_(R)=6.304min, ee %>99%. [α]_(D) ²⁰−47.0 (c=0.10, CHCl₃).

Example 37

7-(3-fluorobenzyl)-3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 and 2

Step 1: A solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (400 mg, 2.1 mmol) and triethylamine (662 mg, 6.5 mmol) inDCM (8 mL) was cooled to 0° C., 2-fluorocyclopropane-1-carbonyl chloride(251 mg, 2.1 mmol) was added dropwise and the mixture was stirred at 0°C. for 0.5 h. The mixture was diluted with water (10 mL), extracted withDCM (20 mL×2). The organic layer was washed with brine (20 mL), driedover Na₂SO₄ and concentrated in vauco. The residue was purified bypreparative TLC (petroleum ether:ethyl acetate=1:1) to givecis-2-fluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide(200 mg, 40% yield) and(1S,2R)-2-fluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide(200 mg, 40% yield) all.

Step 2: To a solution ofcis-2-fluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide(260 mg, 1.1 mmol) in dioxane (10 mL) was added POCl₃ (500 mg, 3.3mmol). The solution was stirred at 80-90° C. for 2 h. The mixture wasconcentrated in vacuo and diluted with NaHCO₃ (30 mL), extracted withDCM (50 mL×2). The organic layer was washed with brine (30 mL), driedover Na₂SO₄ and concentrated in vacuo to give3-(cis-2-fluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine(220 mg, 91% yield).

Step 3: A solution of3-(cis-2-fluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine(220 mg, 994 μmol) in 2N HCl (aq) (5 mL) and dioxane (10 mL) was stirredat 80-90° C. for 1 hour. The mixture was concentrated in vacuo. Theresidue was diluted with NaHCO₃(aq) (30 mL), extracted with DCM (30mL×3). The organic layer was washed with brine (30 mL), dried overNa₂SO₄ and concentrated in vacuo to give3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (200mg, 97% yield).

Step 4: To a solution of3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (200mg, 965 μmol) in anhydrous DMF (10 mL) was added K₂CO₃ (133 mg, 965μmol) and 1-(bromomethyl)-3-fluorobenzene (274 mg, 1.5 mmol). Themixture was stirred at 60-70° C. for 16 h and 80° C. for 21 h. Themixture was cooled and filtered and he filtrate was purified bypreparative LC-MS to give7-(3-fluorobenzyl)-3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(80 mg, 26% yield).

Step 5:7-(3-fluorobenzyl)-3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(80 mg, 253 μmol) was separated by SFC.7-(3-fluorobenzyl)-3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 (25 mg, 30% yield).

¹H NMR (CDCl₃ Varian_H_400 MHz): δ 7.92 (s, 1H), 7.32-7.26 (m, 1H),7.00-6.88 (m, 4H), 5.29-5.15 (m, 2H), 5.02-4.84 (m, 1H), 2.18 (s, 3H),2.12-1.99 (m, 2H), 1.44-1.25 (m, 1H).

LC-MS: t_(R)=2.00 min (method 8), m/z=316.1 [M+H]⁺. SFC: t_(R)=6.53 min,ee %>99%. [α]_(D) ²⁰−84.00 (c=0.10, MeOH).

7-(3-fluorobenzyl)-3-(cis-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (15 mg, 18% yield). ¹H NMR (CDCl₃ Varian_H_400 MHz): δ7.93 (s, 1H), 7.33-7.30 (m, 1H), 7.00-6.90 (m, 4H), 5.31-5.17 (m, 2H),5.04-4.86 (m, 1H), 2.20 (s, 3H), 2.12-2.00 (m, 2H), 1.46-1.42 (m, 1H).

LC-MS: t_(R)=1.99 min (method 8), m/z=316.1 [M+H]⁺. SFC: t_(R)=5.06 min,ee %>99%. [α]_(D) ²⁰+75.00 (c=0.10, MeOH).

Example 38

7-(3-fluorobenzyl)-3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 and 2

Step 1: To a solution oftrans-2-fluoro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)cyclopropane-1-carboxamide(280 mg, 1.1 mmol) in dioxane (10 mL) was added POCl₃ (540 mg, 3.5mmol). The solution was stirred at 80-90° C. for 2 h. The mixture wasconcentrated in vacuo and diluted with NaHCO₃ (30 mL), extracted withDCM (50 mL×2). The organic layer was washed with brine (30 mL), driedover Na₂SO₄ and concentrated in vacuo to give3-(trans-2-fluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine(240 mg, 93% yield).

Step 2: A solution of3-(trans-2-fluorocyclopropyl)-8-methoxy-6-methylimidazo[1,5-a]pyrazine(240 mg, 1.1 mmol) in 2N HCl (aq) (5 mL) and dioxane (10 mL) was stirredat 80-90° C. for 1 hour. The mixture was concentrated in vacuo. Theresidue was diluted with NaHCO₃(aq) (30 mL), extracted with DCM (30mL×3). The organic layer was washed with brine (30 mL), dried overNa₂SO₄ and concentrated in vacuo to give3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(220 mg, 98% yield).

Step 3: To a solution of3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(220 mg, 1.1 mmol) in anhydrous DMF (10 mL) was added K₂CO₃ (293 mg, 2.1mmol) and 1-(bromomethyl)-3-fluorobenzene (300 mg, 1.6 mmol). Themixture was stirred at 60-70° C. for 16 h and 80° C. for 21 h. Themixture was cooled and filtered and the filtrate was purified bypreparative LC-MS to give7-(3-fluorobenzyl)-3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(250 mg, 77% yield).

Step 4:7-(3-fluorobenzyl)-3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(250 mg, 793 μmol) was separated by SFC.

7-(3-fluorobenzyl)-3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 (15 mg, 17% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.81 (s, 1H), 7.31-7.27 (m, 1H), 6.98-6.86 (m,4H), 5.22 (s, 2H), 5.01-4.84 (m, 1H), 2.43-2.38 (m, 1H), 2.19 (s, 3H),1.72-1.65 (m, 1H), 1.58-1.55 (m, 1H).

LC-MS: t_(R)=2.24 min (method 8), m/z=316.1 [M+H]⁺. SFC: t_(R)=2.83 min,ee %>99%. [α]_(D) ²⁰+29.00 (c=0.10, MeOH).

7-(3-fluorobenzyl)-3-(trans-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (45 mg, 17% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.81 (s, 1H), 7.29-7.28 (m, 1H), 6.98-6.86 (m,4H), 5.22 (s, 2H), 5.01-4.84 (m, 1H), 2.45-2.38 (m, 1H), 2.19 (s, 3H),1.71-1.64 (m, 1H), 1.59-1.54 (m, 1H).

LC-MS: t_(R)=2.23 min (method 8), m/z=316.1 [M+H]⁺. SFC: t_(R)=3.69 min,ee %>99%. [α]_(D) ²⁰−31 (c=0.10, MeOH).

Example 39

7-(4-cyclopropoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: A solution of 1-bromo-4-cyclopropoxybenzene (900 mg, 4.22 mmol)in THF (20 mL, anhydrous) was added n-BuLi (2.5 M, 2.6 mL) at −78° C.and stirred at −78° C. for 2 hours under N₂. Then, thereto was addeddropwise DMF (926 mg, 12.66 mmol, anhydrous) at −78° C. and it wasstirred for 2 hours. The solution was quenched with NH₄Cl (aq. 1 mL) at−78° C. and stirred at 0° C. for 0.5 hour. The mixture was diluted withethyl acetate (10 mL). The mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was diluted with ethyl acetate(30 mL), washed with brine (3×15 mL). The organic layer was dried withanhydrous Na2SO4, filtered and concentrated in vacuum to give4-cyclopropoxybenzaldehyde (700 mg). LC-MS: t_(R)=0.800 min (method 2),m/z=162.8 [M+H]⁺.

Step 2: A solution of 4-cyclopropoxybenzaldehyde (700 mg) in MeOH (15mL, anhydrous) was added NaBH₄ (319 mg, 8.44 mmol) at 0° C. and stirredat 0° C. for 1 hour. The solution was quenched with saturated aqueousNH₄Cl (aq. 0.5 mL). The mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=10/1, 1/1) to give (4-cyclopropoxyphenyl)methanol (540 mg, 78%yield).

Step 3: A solution of (4-cyclopropoxyphenyl)methanol (500 mg, 3.1 mmol)and Et₃N (617 mg, 6.1 mmol) in anhydrous DCM (10 mL) was cooled to 0°C., then MsCl (1.41 g, 12.3 mmol) was added dropwise. The solution wasstirred at 0° C. for 0.5 h. The mixture was diluted with water (50 mL),extracted with DCM (50 mL×2). The organic layer was washed with brine(30 mL), dried over Na₂SO₄ and concentrated in vacuo to afford4-cyclopropoxybenzyl methanesulfonate (600 mg, 81% yield).

Step 4: A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(250 mg, 1.07 mmol), 4-cyclopropoxybenzyl methanesulfonate (311 mg, 1.28mmol) and Cs₂CO₃ (698 mg, 2.14 mmol) in DMF (6.0 mL, anhydrous) wasstirred at 60° C. for 12 hours. The mixture was filtered and thefiltrate was concentrated under vacuum. The residue was purified bysilica gel chromatography (petroleum ether/ethyl acetate=10/1, 0/1) togive7-(4-cyclopropoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(320 mg, 77% yield).

¹H NMR (CDCl₃, 400 MHz): δ7.92 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.99 (d,J=8.8 Hz, 2H), 6.73 (s, 1H), 5.17 (s, 2H), 4.12 (d, J=10.4 Hz, 2H),3.71-3.69 (m, 1H), 3.67-3.55 (m, 2H), 3.09-3.07 (m, 1H), 2.21 (s, 3H),2.18-2.03 (m, 2H), 1.88 (d, J=13.2 Hz, 2H), 0.79-0.71 (m, 4H).

LC-MS: t_(R)=2.154 min (method 3), m/z=380.1 [M+H]⁺.

Example 40

7-(4-(difluoromethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(400 mg, 1.7 mmol), 1-(bromomethyl)-4-(difluoromethoxy)benzene (608 mg,2.6 mmol), Cs₂CO₃ (1.11 g, 3.4 mmol) in DMF (50 mL) was stirred at 60°C. for 12 hours. The reaction mixture was concentrated. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=5:1-0:1) to give7-(4-(difluoromethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(360 mg, yield: 52%).

¹H NMR (CDCl₃, 400 MHz): δ 7.91 (s, 1H), 7.20 (d, J=9.2 Hz, 2H), 7.07(d, J=8.0 Hz, 2H), 6.73 (s, 1H), 6.46 (t, J=73.6 Hz, 1H), 5.19 (s, 2H),4.11 (d, J=10.8 Hz, 2H), 3.56 (td, J=12.0, 2.0 Hz, 2H), 3.10-3.04 (m,1H), 2.17-2.06 (m, 5H), 1.86 (d, J=13.2 Hz, 2H).

LC-MS: t_(R)=1.85 min (method 3), m/z=390.1 [M+H]⁺.

Example 41

6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(4-(trifluoromethoxy)benzyl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(400 mg, 1.7 mmol), 1-(bromomethyl)-4-(trifluoromethoxy)benzene (654 mg,2.6 mmol) and Cs₂CO₃ (1.11 g, 3.4 mmol) in DMF (50 mL) was stirred at60° C. for 12 h. The reaction mixture was concentrated. The residue waspurified by silica gel chromatography (petroleum ether:ethylacetate=5:1-0:1) to give6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(4-(trifluoromethoxy)benzyl)imidazo[1,5-a]pyrazin-8(7H)-one(300 mg, yield: 41%).

¹H NMR (CDCl₃, 400 MHz): δ7.91 (s, 1H), 7.25-7.22 (m, 2H), 7.17-7.15 (m,2H), 6.74 (s, 1H), 5.21 (s, 2H), 4.11 (d, J=10.4 Hz, 2H), 3.56 (td,J=11.2, 2.0 Hz, 2H), 3.10-3.04 (m, 1H), 2.17-2.06 (m, 5H), 1.86 (d,J=13.6 Hz, 2H).

LC-MS: t_(R)=2.05 min (method 3), m/z=408.1 [M+H]⁺.

Example 42

7-(4-(cyclopropylmethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: A mixture of 4-hydroxybenzaldehyde (1.0 g, 8.19 mmol),(bromomethyl)cyclopropane (1.33 g, 9.83 mmol) and K₂CO₃ (2.26 g, 16.38mmol) in DMF (10.0 mL, anhydrous) was stirred at 20° C. for 12 hours.The solution was diluted with water (20 mL). The aqueous phase wasextracted with ethyl acetate (60 mL×3). The combined organic phase waswashed with brine (20 mL×1), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=10/1, 1/1) to give4-(cyclopropylmethoxy)benzaldehyde (1.3 g, 87% yield).

Step 2: A solution of 4-(cyclopropylmethoxy)benzaldehyde (1.3 g, 7.4mmol) in MeOH (30 mL) was cooled to 0° C., then NaBH₄ (558 mg, 14.8mmol) was added and the mixture was stirred at 0° C. for 1 hour. Themixture was quenched with sat. brine (aq) (50 mL), extracted with EtOAc(50 mL×2). The organic layer was washed with brine, dried over Na₂SO₄and concentrated in vacuo to afford(4-(cyclopropylmethoxy)phenyl)methanol (1.21 g, 92% yield).

Step 3. A solution of (4-(cyclopropylmethoxy)phenyl)methanol (800 mg,4.5 mmol) and Et₃N (907 mg, 9.0 mmol) in DCM (10 mL) was cooled to 0°C., then MsCl (617 mg, 5.4 mmol) was added dropwise. The solution wasstirred at 0° C. for 0.5 h. The mixture was diluted with water (50 mL),extracted with DCM (50 mL×2). The organic layer was washed with brine(30 mL), dried over Na₂SO₄ and concentrated in vacuo to afford4-(cyclopropylmethoxy)benzyl methanesulfonate (760 mg, 66% yield).

Step 4: A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(300 mg, 1.29 mmol), 4-(cyclopropylmethoxy)benzyl methanesulfonate (429mg, 1.68 mmol) and Cs₂CO₃ (841 mg, 2.58 mmol) in DMF (6 mL, anhydrous)was stirred at 60° C. for 12 hours. The mixture was filtered and thefiltrate was concentrated under vacuum. The residue was purified bysilica gel chromatography (column height: 250 mm, diameter: 100 mm,100-200 mesh silica gel, Petroleum ether/Ethyl acetate=10/1, 0/1) togive7-(4-(cyclopropylmethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(360 mg, 68% yield).

¹H NMR (CDCl₃, 400 MHz): δ7.92 (s, 1H), 7.14 (d, J=8.8 Hz, 2H), 6.85 (d,J=9.2 Hz, 2H), 6.73 (s, 1H), 5.16 (s, 2H), 4.12 (d, J=10.8 Hz, 2H), 3.77(d, J=6.8 Hz, 2H), 3.61-3.55 (m, 2H), 3.10-3.04 (m, 1H), 2.20-2.09 (m,5H), 1.88 (d, J=13.2 Hz, 2H), 1.27-1.24 (m, 1H), 0.66-0.61 (m, 2H),0.35-0.33 (m, 2H).

LC-MS: t_(R)=2.238 min (method 3), m/z=394.1 [M+H]⁺.

Example 43

7-benzyl-6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (100mg, 404 μmol), bromomethylbenzene (83 mg, 485.26 μmol) and Cs₂CO₃ (264mg, 809 μmol) in DMF (3.0 mL) was stirred at 60° C. for 16 hours. Thereaction mixture was filtered and the filtrate was concentrated. Theresidue was purified by HPLC to give7-benzyl-6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(56.0 mg, 41.0% yield).

¹H NMR (CDCl₃ 400 MHz): δ 57.91 (s, 1H), 7.32-7.26 (m, 3H), 7.22-7.15(m, 2H), 6.69 (s, 1H), 5.25 (s, 2H), 4.12 (d, J=10.8 Hz, 2H), 3.62-3.56(m, 2H), 3.14-3.07 (m, 1H), 2.53-2.48 (m, 2H), 2.17-2.09 (m, 2H), 1.89(d, J=13.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H).

LC-MS: t_(R)=2.042 min (method 3), m/z=338.2 [M+H]⁺.

Example 44

6-ethyl-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (100mg, 404 μmol), 1-(bromomethyl)-4-methoxy-benzene (98 mg, 485 μmol) andCs₂CO₃ (264 mg, 809 μmol) in DMF (5.0 mL) was stirred at 60° C. for 16hours. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by HPLC to give6-ethyl-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(65 mg, 42.3% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.91 (s, 1H), 7.12 (d, J=8.0 Hz, 2H), 6.83 (d,J=7.6 Hz, 2H), 6.68 (s, 1H), 5.18 (s, 2H), 4.12 (d, J=11.6 Hz, 2H), 3.77(s, 3H), 3.61-3.55 (m, 2H), 3.12-3.07 (m, 1H), 2.56-2.51 (m, 2H),2.16-2.08 (m, 2H), 1.88 (d, J=13.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H).

LC-MS: t_(R)=2.050 min (method 3), m/z=368.2 [M+H]⁺.

Example 45

3-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 428.69 μmol), 3-(bromomethyl)benzonitrile (126 mg, 643.03 μmol)and Cs₂CO₃ (279 mg, 858 μmol) in DMF (3 mL) was stirred at 70° C. for 6hours. The mixture was filtered and the filtrate was concentrated undervacuum. The residue was purified by preparative LC-MS to afford3-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile(35 mg, 23% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.95 (s, 1H), 7.59 (d, J=6.8 Hz, 1H),7.51-7.45 (m, 3H), 6.80 (s, 1H), 5.25 (s, 2H), 4.14 (d, J=10.8 Hz, 2H),3.63-3.57 (m, 2H), 3.14-3.08 (m, 1H), 2.19-2.10 (m, 5H), 1.91 (d, J=13.2Hz, 2H).

LC-MS: t_(R)=2.164 min (method 3), m/z=349.1 [M+H]⁺.

Example 46

4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 428.69 μmol), 4-(bromomethyl)benzonitrile (126 mg, 643.04 μmol)and Cs₂CO₃ (279 mg, 858 μmol) in DMF (3 mL) was stirred at 60° C. for 2hours. The mixture was filtered and the filtrate was concentrated undervacuum. The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=10/1, 1/5) to afford4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile(65 mg, 43% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.94 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.32 (d,J=8.4 Hz, 2H), 6.79 (s, 1H), 5.28 (s, 2H), 4.14 (d, J=11.2 Hz, 2H),3.62-3.56 (m, 2H), 3.13-3.07 (m, 1H), 2.19-2.09 (m, 5H), 1.89 (d, J=13.2Hz, 2H).

LC-MS: t_(R)=2.160 min (method 3), m/z=349.2 [M+H]⁺.

Example 47

N-(4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)phenyl)acetamide

Step 1: A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 858 μmol), 1-(bromomethyl)-4-nitrobenzene (278 mg, 1.29 mmol)and Cs₂C₀₃ (559 mg, 1.71 mmol) in DMF (4 mL) was stirred at 60° C. for 2hours. The mixture was filtered and the filtrate was concentrated undervacuum. The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=10/1, 1/5) to afford6-methyl-7-(4-nitrobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(270 mg, 85% yield). LC-MS: t_(R)=0.612 min (method 2), m/z=368.8[M+H]⁺.

Step 2: A mixture of6-methyl-7-(4-nitrobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 542.90 μmol), Fe (152 mg, 2.71 mmol), NH₄Cl (88 mg, 1.63 mmol)and MeOH (10 mL) in H₂O (10 mL) was stirred at 70° C. for 4 hours. Themixture was filtered and the filtrate was concentrated under vacuum. Theresidue was purified by silica gel chromatography(dichloromethane/methanol=I/O, 15/1) to afford7-(4-aminobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(170 mg, 93% yield).

LC-MS: t_(R)=0.287 min (method 2), m/z=338.9 [M+H]⁺.

Step 3: A mixture of7-(4-aminobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(120 mg, 354.61 μmol), acetyl acetate (60 mg, 588.65 μmol) andtriethylamine (144 mg, 1.42 mmol) in dioxane (10 mL) was stirred at 90°C. for 6 hours. The solution was quenched with water (2 mL) and stirredat 60° C. for 2 hours. Then it was concentrated under vacuum. Theresidue was purified by silica gel chromatography(dichloromethane/methanol=I/O, 15/1) to affordN-(4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)phenyl)acetamide(120 mg, 86.52% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.17 (d,J=8.4 Hz, 2H), 6.74 (s, 1H), 5.19 (s, 2H), 4.13 (d, J=10.4 Hz, 2H), 3.59(t, J=10.0 Hz, 2H), 3.12-3.06 (m, 1H), 2.19-2.09 (m, 8H), 1.88 (d,J=13.2 Hz, 2H).

LC-MS: t_(R)=1.593 min (method 3), m/z=381.1 [M+H]⁺.

Example 48

7-(4-chloro-3-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a suspension of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 429 μmol) in dry DMF (2 mL) was added Cs₂CO₃ (279 mg, 858 μmol)and 4-(bromomethyl)-1-chloro-2-methoxybenzene (151 mg, 643 μmol). Themixture was purged with N₂ for 2 min and heated at 60° C. for 16 hours.The mixture was concentrated. DCM (30 ml) was added to the residue. Itwas filtered and the filter cake was washed with DCM (20 mL). Thefiltrate was concentrated and purified by flash chromatography on silicagel (10%˜100% ethyl acetate in petroleum ether) to give7-(4-chloro-3-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(99.01 mg, 60% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.93 (s, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.85 (d,J=1.6 Hz, 1H), 6.75 (s, 1H), 6.72-6.69 (m, 1H), 5.17 (s, 2H), 4.14-4.11(m, 2H), 3.86 (s, 3H), 3.61-3.55 (m, 2H), 3.10-3.06 (m, 1H), 2.20 (s,3H), 2.18-2.11 (m, 2H), 1.89-1.86 (m, 2H).

LC-MS: t_(R)=2.466 min (method 3), m/z=388.1 [M+H]⁺.

Example 49

7-(2-ethylbenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: A solution of (2-ethylphenyl)methanol (500 mg, 3.67 mmol) andtriethylamine (742 mg, 7.34 mmol) in DCM (5 mL) was added MsCl (1.0 g,8.73 mmol) at 0° C. and stirred at 0° C. for 0.5 hour. Then it wasstirred at 20° C. for 1 hour. The mixture was quenched with water (0.5mL), and diluted with DCM (10 mL). The mixture was added NaHCO₃ (aq.)until pH=8.

The organic layer was washed with water (3×5 mL), dried with anhydrousNa₂SO₄, filtered and concentrated under vacuum to give 2-ethylbenzylmethanesulfonate (600 mg), which was used into the next step withoutfurther purification.

Step 2: A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(150 mg, 643 μmol), 2-ethylbenzyl methanesulfonate (276 mg) and Cs₂CO₃(419 mg, 1.29 mmol) in DMF (5 mL) was stirred at 60° C. for 12 hours.The mixture was filtered and the filtrate was concentrated under vacuum.The residue was purified by preparative LC-MS to afford7-(2-ethylbenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(90 mg, 40% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.93 (s, 1H), 7.25-7.21 (m, 2H), 7.14-7.10 (m,1H), 6.81-6.77 (m, 2H), 5.25 (s, 2H), 4.14 (d, J=11.2 Hz, 2H), 3.60 (t,J=12.0 Hz, 2H), 3.15-3.09 (m, 1H), 2.78-2.72 (m, 2H), 2.21-2.13 (m, 5H),1.91 (d, J=13.6 Hz, 2H), 1.31 (t, J=7.6 Hz, 3H).

LC-MS: t_(R)=2.533 min (method 3), m/z=352.2 [M+H]⁺.

Example 50

7-(benzo[d][1,3]dioxol-5-ylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a suspension of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 429 μmol) in dry DMF (2 mL) was added Cs₂C₀₃ (279 mg, 858 μmol)and 5-(bromomethyl)benzo[d][1,3]dioxole (138 mg, 643 μmol). The mixturewas bubbled with N₂ for 2 min and heated at 60° C. for 16 hours. Themixture was concentrated. DCM (30 mL) was added to the residue. It wasfiltered and the filter cake was washed with DCM (20 mL). The filtratewas concentrated and purified by flash chromatography on silica gel(10%˜100% ethyl acetate in petroleum ether) to give7-(benzo[d][1,3]dioxol-5-ylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(81.74 mg, 52% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 6.76-6.69 (m, 4H), 5.95-5.93 (m,2H), 5.13 (s, 2H), 4.14-4.11 (m, 2H), 3.61-3.55 (m, 2H), 3.10-3.05 (m,1H), 2.21 (s, 3H), 2.20-2.10 (m, 2H), 1.90-1.86 (m, 2H).

LC-MS: t_(R)=2.245 min (method 3), m/z=368.2 [M+H]⁺.

Example 51

7-(3-chloro-4-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 427 μmol), 4-(bromomethyl)-2-chloro-1-methoxybenzene (151 mg,643 μmol) and Cs₂CO₃ (279 mg, 858 μmol) in DMF (3 mL) was stirred at 60°C. for 2 hours. The mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by silica gelchromatography (detroleum ether/ethyl acetate=10/1, 0/1) to afford7-(3-chloro-4-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(110 mg, 65% yield).

¹H NMR (CDCl₃ 400 MHz): δ 57.93 (s, 1H), 7.24 (d, J=0.8 Hz, 1H),7.12-7.10 (m, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.75 (s, 1H), 5.15 (s, 2H),4.13 (d, J=10.4 Hz, 2H), 3.88 (s, 3H), 3.62-3.56 (m, 2H), 3.12-3.06 (m,1H), 2.20-2.09 (m, 5H), 1.89 (d, J=13.2 Hz, 2H).

LC-MS: t_(R)=2.414 min (method 3), m/z=388.1 [M+H]⁺.

Example 52

7-(4-aminobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A solution ofN-(4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)phenyl)acetamide(100 mg, 263 μmol), NaOH (63 mg, 1.58 mmol) and MeOH (1 mL) in H₂O (1mL) was stirred at 90° C. for 12 hours. The solution was added KHSO₄(aq.) until pH=7 and concentrated under vacuum. The residue was purifiedby preparative TLC (DCM:MeOH=10:1). to afford7-(4-aminobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(50 mg, 56% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.91 (s, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.71 (s,1H), 6.63 (d, J=8.4 Hz, 2H), 5.12 (s, 2H), 4.13 (d, J=12.0 Hz, 2H), 3.67(brs, 2H), 3.61-3.55 (m, 4H), 3.10-3.05 (m, 1H), 2.21 (s, 3H), 2.17-2.08(m, 2H), 1.88 (d, J=13.2 Hz, 2H).

LC-MS: t_(R)=1.273 min (method 3), m/z=339.1 [M+H]⁺.

Example 53

7-(4-hydroxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

A solution of7-(4-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(2.0 g, 5.66 mmol) in DCM (32 mL) was added BBr₃ (4.3 g, 16.98 mmol) at0° C. and stirred at 20° C. for 3 hours. The solution was quenched withH₂O (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour and thento it was added NaHCO₃ (saturated aqueous) until pH=6. The mixture wasconcentrated under vacuum. The residue was diluted with DCM (20 mL) andMeOH (2 mL). Then it was filtered and the filtrate was concentratedunder vacuum. The residue was added into KOH (60 mL, 2 M, aq.) at 20° C.and stirred at 50° C. for 1 hour. The solution was added KHSO₄(saturated aqueous) until pH=6, the mixture was concentrated undervacuum. The residue was purified by silica gel chromatography(dichloromethane/methanol=I/O, 15/1) to afford7-(4-hydroxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(460 mg, 24% yield).

¹H NMR (DMSO Varian_H_400 MHz): δ 9.39 (s, 1H), 7.70 (s, 1H), 7.46 (s,1H), 6.99 (d, J=8.4 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 5.06 (s, 2H),3.96-3.93 (m, 2H), 3.52-3.45 (m, 2H), 3.29-3.16 (m, 1H), 2.15 (s, 3H),1.83-1.77 (m, 4H).

LC-MS: t_(R)=1.62 min (method 8), m/z=340.1 [M+H]⁺.

Example 54

6-ethyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: A mixture of methyl 1H-imidazole-5-carboxylate (1.6 g, 13 mmol),1-bromobutan-2-one (2.0 g, 13 mmol) and K₂CO₃ (3.5 g, 25 mmol) inacetone (20 mL) was stirred at 40° C. for 12 hours. The mixture wasconcentrated under vacuum. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=10/1, 0/1) to give methyl1-(2-oxobutyl)-1H-imidazole-5-carboxylate (750 mg, 30% yield).

Step 2: A mixture of methyl 1-(2-oxobutyl)-1H-imidazole-5-carboxylate(700 mg, 3.59 mmol), NBS (831 mg, 4.67 mmol), and AIBN (118 mg, 718μmol) in CHCl₃ (20 mL) was stirred at 50° C. for 12 hours. The mixturewas concentrated under vacuum. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=10/1, 1/2) to give methyl2-bromo-1-(2-oxobutyl)-1H-imidazole-5-carboxylate (650 mg, 66% yield).LC-MS: t_(R)=0.585 min (method 2), m/z=274.7 [M+H]⁺

Step 3: A mixture of methyl2-bromo-1-(2-oxobutyl)-1H-imidazole-5-carboxylate (650 mg, 2.36 mmol)and NH₄OAc (727.64 mg, 9.44 mmol) in 1,4-dioxane (15 mL) was stirred at90° C. for 3 days. The mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatography (petroleum ether/ethylacetate=10/1, 1/1) to give3-bromo-6-ethylimidazo[1,5-a]pyrazin-8(7H)-one (500 mg, 88% yield).LC-MS: t_(R)=0.542 min (method 2), m/z=241.8 [M+H]⁺

Step 4: A mixture of 3-bromo-6-ethylimidazo[1,5-a]pyrazin-8(7H)-one (500mg, 2.07 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(522 mg, 2.48 mmol), K₂CO₃ (572 mg, 4.14 mmol), Pd(dppf)Cl₂ (303 mg, 414μmol) and H₂O (5 mL) in 1,4-dioxane (20 mL) was stirred at 100° C. for12 hours. The mixture was filtered and the filtrate was concentratedunder vacuum. The residue was purified by silica gel chromatography(Dichloromethane/Methanol=1/0, 15/1) to give3-(3,6-dihydro-2H-pyran-4-yl)-6-ethylimidazo[1,5-a]pyrazin-8(7H)-one(400 mg, 78.78% yield). LC-MS: t_(R)=0.430 min (method 2), m/z=245.8[M+H]⁺

Step 5: A mixture of3-(3,6-dihydro-2H-pyran-4-yl)-6-ethylimidazo[1,5-a]pyrazin-8(7H)-one(400 mg, 1.63 mmol) and Pd/C (dry, 10% Pd, 20 mg) in THF (15 mL) wasstirred at 15° C. for 4 hours under H₂ (15 psi). The mixture wasfiltered and the filtrate was concentrated under vacuum to afford6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (300mg, 74% yield). LC-MS: t_(R)=1.324 min (method 9), m/z=248.0 [M+H]⁺.

Step 6: A mixture of6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (300mg, 1.21 mmol), 1-(bromomethyl)-3-fluorobenzene (297 mg, 1.57 mmol) andK₂CO₃ (334 mg, 2.42 mmol) in DMF (20 mL) was stirred at 60° C. for 12hours. The mixture was filtered and the filtrate was concentrated undervacuum. The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=3/1, 0/1) to afford6-ethyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(150 mg, 34% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.94 (s, 1H), 7.32-7.27 (m, 1H), 6.98-6.94 (m,2H), 6.86 (d, J=9.6 Hz, 1H), 6.72 (s, 1H), 5.25 (s, 2H), 4.14 (d, J=11.2Hz, 2H), 3.64-3.58 (m, 2H), 3.15-3.09 (m, 1H), 2.53-2.48 (m, 2H),2.18-2.13 (m, 2H), 1.91 (d, J=13.2 Hz, 2H), 1.25 (t, J=7.2 Hz, 2H).

LC-MS: t_(R)=2.475 min (method 3), m/z=356.1 [M+H]⁺.

Example 55

7-(4-methoxybenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomers 1, 2, 3 and 4

Step 1: To a cooled (0° C.) solution of2-methyltetrahydrofuran-3-carboxylic acid (110 mg, 845 μmol) in dry DCM(2 mL) was added oxalyl dichloride (107 mg, 845 μmol) dropwise. Then onedrop of DMF was added and the mixture was stirred at 26° C. for 1 hour.The solution of 2-methyltetrahydrofuran-3-carbonyl chloride (126 mg) inDCM (2 mL) was directly used for the next step.

Step 2: To a cooled (0° C.) solution of2-methyltetrahydrofuran-3-carbonyl chloride (160 mg, 844 μmol, HCl) indry DCM (5 mL) was added triethylamine (256 mg, 2.53 mmol) and(3-methoxy-5-methylpyrazin-2-yl)methanamine (125 mg, 843.70 μmol) in DCM(2 mL) dropwise. The mixture was stirred at 26° C. for 1 hour. LCMSshowed the reaction was completed. Water (5 mL) was added to themixture. The mixture was extracted with DCM (30 mL×2). The combinedorganic layer was washed with H₂O (20 mL), brine (20 mL), dried overNa₂SO₄, filtered and concentrated. The crude product was purified byflash chromatography on silica gel (10-50% ethyl acetate in petroleumether) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyltetrahydrofuran-3-carboxamide(100 mg, 45% yield) as a light yellow oil.

Step 3: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyltetrahydrofuran-3-carboxamide(150 mg, 565 μmol) in dry dioxane (5 mL) was added POCl₃ (173 mg, 1.13mmol). The mixture was heated at 80° C. for 2 hours. The mixture wascooled to 26° C. and the brown solution of8-methoxy-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine(140 mg) in dioxane (5 mL) was directly used for the next step.

Step 4: To a solution of8-methoxy-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazine(140 mg, 566 μmol) in dioxane (5 mL) was added 2 N HCl (2 M, 2 mL). Themixture was heated at 80° C. for 1 hour. The mixture was cooled to 25°C., adjusted to pH=7 by saturated aqueousNaHCO₃ and extracted with DCM(20 mL×2). The combined organic phases were washed with H₂O (20 mL),brine (20 mL), dried over Na₂SO₄, filter and concentrated to give6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(131 mg).

Step 5: To a solution of6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(131 mg, 562 μmol) in dry DMF (5 mL) was added1-(bromomethyl)-4-methoxybenzene (169 mg, 842 μmol) and Cs₂CO₃ (366 mg,1.12 mmol). The mixture was heated at 60° C. for 16 hours. The mixturewas concentrated and water (10 mL) was added. The mixture was extractedwith DCM (30 mL×2). The combined organic layer was washed with H₂O (30mL×2), brine (30 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on silica gel (10%˜100%ethyl acetate in petroleum ether) to give7-(4-methoxybenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(90 mg, 45% yield).

7-(4-methoxybenzyl)-6-methyl-3-(2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 283 μmol) was purified by SFC.

Stereoisomer 1: (9.4 mg, 9% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.74 (s, 1H), 5.16 (s, 2H), 4.30-4.26 (m, 1H), 4.12-4.04(m, 2H), 3.78 (s, 3H), 3.09-3.03 (m, 1H), 2.46-2.34 (m, 2H), 2.20 (s,3H), 1.32 (d, J=6.0 Hz, 3H).

LC-MS: t_(R)=2.074 min (method 13), m/z=354.1 [M+H]⁺. SFC: t_(R)=5.177min, ee %>99%. [α]_(D) ²⁰−26 (c=0.10, DCM).

Stereoisomer 2: (7.3 mg, 7% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.73 (s, 1H), 5.16 (s, 2H), 4.30-4.26 (m, 1H), 4.10-4.02(m, 2H), 3.78 (s, 3H), 3.09-3.03 (m, 1H), 2.44-2.35 (m, 2H), 2.20 (s,3H), 1.32 (d, J=6.0 Hz, 3H).

LC-MS: t_(R)=2.072 min (method 13), m/z=354.1 [M+H]⁺. SFC: t_(R)=5.458min, ee %=99.7%. [c]_(D) ²⁰+24 (c=0.10, DCM).

Stereoisomer 3: (39.7 mg, 40% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.78 (s, 1H), 5.22-5.10 (m, 2H), 4.31-4.26 (m, 2H),3.88-3.82 (m, 1H), 3.77 (s, 3H), 3.70-3.60 (m, 1H), 2.71-2.67 (m, 1H),2.43-2.40 (m, 1H), 2.19 (s, 3H), 0.87 (d, J=4.4 Hz, 3H).

LC-MS: t_(R)=1.983 min (method 13), m/z=354.1 [M+H]⁺. SFC: t_(R)=5.932min, ee %=98.8%. [α]_(D) ²⁰+48 (C=0.10, DCM).

Stereoisomer 4: (26.4 mg, 26% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.78 (s, 1H), 5.22-5.09 (m, 2H), 4.32-4.26 (m, 2H),3.87-3.85 (m, 1H), 3.77 (s, 3H), 3.68-3.64 (m, 1H), 2.70-2.65 (m, 1H),2.42-2.37 (m, 1H), 2.19 (s, 3H), 0.87 (d, J=6.4 Hz, 3H).

LC-MS: t_(R)=1.983 min (method 13), m/z=354.1 [M+H]⁺. SFC: t_(R)=6.570min, ee %=99.6%. [α]_(D) ²⁰−64 (c=0.10, DCM).

Example 56

7-(4-methoxybenzyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of3-bromo-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (500mg, 1.44 mmol, 1 eq) in THF (10 mL) was added Ni(dppp)Cl₂ (327.83 mg,604.80 μmol, 0.42 eq) at 0° C. over 10 min, then at −78° C. for 10 min.propylmagnesium bromide (1 M, 3 mL, 2.1 eq) was added dropwise at 0° C.The resulting mixture was stirred at 0° C. for 1.5 hour. The reactionwas quenched by saturated NH₄Cl aqueous solution (5 mL). The residue waspurified by silica column chromatography (Gradient: 0-50, EtOAc in PEwith 1% triethylamine) to give 220 mg of crude product. The crudeproduct was purified by preparative TLC (PE:EtOAc=1:1 with 1%triethylamine). The residue was washed with hexane (3 mL) and filteredand the filter cake was dried under vacuum to give7-(4-methoxybenzyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one (82mg, 18% yield).

¹HNMR (CDCl₃, 400 MHz): δ7.90 (s, 1H), 7.16 (d, J=8.8, 2H), 6.85 (d,J=8.8, 2H), 6.68 (s, 1H), 5.17 (s, 2H), 3.78 (s, 3H), 2.82 (t, J=7.2,2H), 2.19 (s, 3H), 1.90-1.81 (m, 2H), 1.03 (t, J=7.2, 3H).

LC-MS: t_(R)=1.927 min (method 13), m/z=312.1 [M+H]⁺.

Example 57

7-((6-methoxypyridin-3-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Into a vial was added6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 0.86 mmol), 5-(chloromethyl)-2-methoxypyridine (162 mg, 1.03mmol), cesium carbonate (559 mg, 1.72 mmol) and sodium iodide (154 mg,1.03 mmol) in DMF (9.44 g, 10 ml, 129 mmol). The reaction was stirredovernight at 70° C. To the reaction was added ethylacetate, and it wasfiltered and concentrated. The reaction was purified by chromatographyon silicagel to obtain7-((6-methoxypyridin-3-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(127 mg, 0.358 mmol) in 42% yield.

¹H NMR (600 MHz, CDCl₃) δ 8.06 (dd, J=2.5, 0.8 Hz, 1H), 7.91 (d, J=0.6Hz, 1H), 7.55 (dd, J=8.6, 2.5 Hz, 1H), 6.74 (t, J=1.1 Hz, 1H), 6.71 (dd,J=8.6, 0.7 Hz, 1H), 5.15 (s, 2H), 4.12 (m, 2H), 3.91 (s, 3H), 3.58 (td,J=11.7, 2.2 Hz, 2H), 3.07 (tt, J=11.4, 3.9 Hz, 1H), 2.25 (d, J=1.2 Hz,3H), 2.12 (dtd, J=13.7, 11.6, 4.3 Hz, 2H), 1.87 (ddd, J=13.5, 4.2, 2.1Hz, 2H).

LC-MS: t_(R)=0.38 min (method 6), m/z=355.2 [M+H]⁺.

Example 58

6,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 428.69 μmol, 1 eq) in DMSO (2 mL) was added Cs₂CO₃ (139.68 mg,428.69 μmol, 1 eq) and methyliodide (121.70 mg, 858 μmol, 53.38 μL, 2eq). The mixture was stirred at 50° C. for 12 hour. The reaction mixturewas diluted with H₂O (25 mL) and extracted with DCM (50 mL×2). Thecombined organic layers were washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by preparative TLC (ethyl acetate).6,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(73 mg, 68% yield, 98% purity) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.87 (s, 1H), 6.76 (s, 1H), 4.13 (d, J=11.2Hz, 2H), 3.59 (t, J=11.2 Hz, 2H), 3.46 (s, 3H), 3.11-3.05 (m, 1H), 2.28(s, 3H), 2.16-2.08 (m, 2H), 1.88 (d, J=14.0 Hz, 2H).

LC-MS: t_(R)=1.300 min (method 13), m/z=248.1 [M+H]⁺.

Example 59

7-ethyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 429 μmol, 1 eq) in anhydrous DMF (2 mL) was added K₂CO₃ (119mg, 858 μmol, 2 eq) and iodoethane (134 mg, 858 μmol, 69 μL, 2 eq). Themixture was stirred at 50° C. for 12 hour. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with H₂O(20 mL) and extracted with EA (40 mL×2). The combined organic layerswere washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford a residue.7-ethyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 34% yield, 96% purity) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.85 (s, 1H), 6.73 (s, 1H), 4.12 (d, J=10.8Hz, 2H), 4.03-3.99 (m, 2H), 3.58 (t, J=10.8 Hz, 2H), 3.10-3.04 (m, 1H),2.30 (s, 3H), 2.16-2.07 (m, 2H), 1.87 (d, J=13.2 Hz, 2H), 1.29 (t, J=6.8Hz, 3H).

LC-MS: t_(R)=1.490 min (method 11), m/z=262.1 [M+H]⁺.

Example 60

6-methyl-7-propyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 429 μmol, 1 eq) in anhydrous DMF (2 mL) was added K₂CO₃ (119mg, 858 μmol, 2 eq) and 1-bromopropane (105 mg, 858 μmol, 78.11 μL, 2eq). The mixture was stirred at 50° C. for 12 hours. The reactionmixture was concentrated under reduced pressure to remove DMF. Theresidue was diluted with H₂O (20 mL) and extracted with EA (40 mL×2).The combined organic layers were washed with brine (15 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by preparative TLC (ethyl acetate).6-methyl-7-propyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(45 mg, 37% yield, 98% purity) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.85 (s, 1H), 6.72 (s, 1H), 4.12 (d, J=10.4Hz, 2H), 3.88 (t, J=8.0 Hz, 2H), 3.62-3.56 (m, 2H), 3.10-3.07 (m, 1H),2.28 (s, 3H), 2.14-2.09 (m, 2H), 1.87 (d, J=13.2 Hz, 2H), 1.73-1.67 (m,2H), 1.00 (t, J=7.2 Hz, 3H).

LC-MS: t_(R)=1.666 min (method 11), m/z=276.1 [M+H]⁺.

Example 61

7-isopropyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(350 mg, 1.50 mmol, 1 eq) in anhydrous DMF (4 mL) was added Cs₂C₀₃ (978mg, 3 mmol, 2 eq) and 2-iodopropane (510 mg, 3 mmol, 300 μL, 2 eq). Themixture was stirred at 50° C. for 12 hours. The reaction mixture wasconcentrated under reduced pressure to remove DMF. The residue wasdiluted with H₂O (15 mL) and extracted with EtOAc (40 mL×2). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by preparative TLC (ethyl acetate).7-isopropyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(68 mg, 16% yield, 96% purity) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.81 (s, 1H), 6.67 (s, 1H), 4.40 (m, 1H), 4.12(d, J=11.6 Hz, 2H), 3.58 (t, J=11.3 Hz, 2H), 3.09-3.03 (m, 1H), 2.27 (s,3H), 2.14-2.06 (m, 2H), 1.86 (d, J=13.2 Hz, 2H), 1.62-1.61 (m, 6H).

LC-MS: t_(R)=1.576 min (method 13), m/z=276.1 [M+H]⁺.

Example 62

7-isopentyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a solution of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 428.69 μmol, 1 eq) in anhydrous DMF (2 mL) was added K₂CO₃(118.50 mg, 858 μmol, 2 eq) and 1-bromo-3-methylbutane (129.50 mg, 858μmol, 108 μL, 2 eq). The mixture was stirred at 50° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure to remove DMF.The residue was diluted with H₂O (20 mL) and extracted with EtOAc (40mL×2). The combined organic layers were washed with brine (15 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by preparative TLC (ethyl acetate).7-isopentyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(65 mg, 50% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.84 (s, 1H), 6.73 (s, 1H), 4.12 (d, J=10.4Hz, 2H), 3.93 (t, J=8.0 Hz, 2H), 3.61-3.55 (m, 2H), 3.08-3.04 (m, 1H),2.28 (s, 3H), 2.10-2.09 (m, 2H), 1.87 (d, J=14.0 Hz, 2H), 1.74-1.69 (m,1H), 1.56-1.52 (m, 2H), 1.00-0.98 (m, 6H).

LC-MS: t_(R)=1.968 min (method 13), m/z=304.2 [M+H]⁺.

Example 63

7-(cyclopentylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

To a mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(150 mg, 0.64 mmol) and (bromomethyl)cyclopentane (157 mg, 0.96 mmol) inDMSO (2 mL) was added Cs₂CO₃ (419 mg, 1.29 mmol). The mixture wasstirred at 60° C. for 12 hours. The mixture was diluted with water (10mL) and extracted with DCM (5 mL×3). The combine organic layer waswashed with water (5 mL×2) and dried over Na₂SO₄. The organic layers wasevaporated under vacuum. The residue was purified by preparative TLC(ethyl acetate) to give7-(cyclopentylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(95 mg, 46% yield). ¹HNMR (CDCl₃, 400 MHz): δ 7.85 (s, 1H), 6.72 (s,1H), 4.14-4.11 (m, 2H), 3.91 (d, J=7.6 Hz, 2H), 3.61-3.56 (m, 2H),3.12-3.05 (m, 1H), 2.29 (s, 3H), 2.27-2.25 (m, 1H), 2.14-2.10 (m, 2H),1.90-1.86 (m, 2H), 1.71-1.54 (m, 6H), 1.34-1.32 (m, 2H).

LC-MS: t_(R)=1.98 min (method 13), m/z=316.2 [M+H]⁺.

Example 64

2-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile

A mixture of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100 mg, 429 μmol), 2-(bromomethyl)benzonitrile (126 mg, 643 μmol) andCs₂CO₃ (279 mg, 857 μmol) in DMF (3.0 mL) was stirred at 70° C. for 6hours. The mixture was filtered and the filtrate was concentrated undervacuum. The residue was purified by silica gel chromatography (Petroleumether/Ethyl acetate=10/1, 0/1) to afford2-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile(92 mg, 59% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.96 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.55 (t,J=7.2 Hz, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.80 (s,1H), 5.45 (s, 2H), 4.14 (d, J=12.0 Hz, 2H), 3.63-3.57 (m, 2H), 3.14-3.08(m, 1H), 2.20-2.09 (m, 5H), 1.90 (d, J=13.2 Hz, 2H).

LC-MS: t_(R)=2.202 min (method 3), m/z=349.1 [M+H]⁺.

Example 65

7-(cycloheptylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of cycloheptanecarboxylic acid (500 mg, 3.52 mmol)in THF (40 mL) was added LiAlH₄ (401 mg, 10.6 mmol) in portions at 0° C.The mixture was stirred at 65° C. for 3 hours. The reaction was quenchedwith H₂O (0.4 mL) and 10% NaOH (0.4 mL, aq). To the mixture was addedNa₂SO₄. The mixture was filtered. The filtrate was concentrated. Theresidue was purified by flash silica gel chromatography to givecycloheptylmethanol (383 mg, 85% yield).

¹H NMR (CDCl₃ 400 MHz): δ 3.43 (d, J=6.4 Hz, 2H), 1.80-1.62 (m, 5H),1.56-1.40 (m, 4H), 1.31 (br, s, 1H), 1.84 (s, 3H), 1.10-1.22 (m, 2H).

Step 2: To a solution of cycloheptylmethanol (313 mg, 2.44 mmol) andtriethylamine (494 mg, 4.88 mmol) in DCM (5 mL) was added MsCl (490 mg,4.28 mmol) at 0° C. and it was stirred at 20° C. for 40 min. Thesolution was washed with NaHCO₃ (saturated aqueous 5 mL×4), water (5mL×2), brine (3 mL) and then was dried over Na₂SO₄, filtered andconcentrated to give cycloheptylmethyl methanesulfonate (381 mg) whichwas used in the next step directly without further purification.

Step 3: To a solution of6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(150 mg, 643 μmol) and cycloheptylmethyl methanesulfonate (159 mg, 772μmol) in DMF (3 mL) was added Cs₂CO₃ (419 mg, 1.29 mmol). The mixturewas stirred at 60° C. for 6 hours. The mixture was diluted with DCM (20mL) and washed with water (5 mL×2), brine (10 mL), dried over Na₂SO₄,filtered and concentrated. The residue was purified by flash silica gelchromatography and then was purified by preparative LC-MS to give7-(cycloheptylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(25.15 mg, 11% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.84 (s, 1H), 6.71 (s, 1H), 4.12 (d, J=5.2 Hz,2H), 3.77 (d, J=3.6 Hz, 2H), 3.65-3.52 (m, 2H), 3.15-3.02 (m, 1H), 2.26(s, 3H), 2.17-2.07 (m, 2H), 2.07-2.98 (m, 1H), 1.87 (d, J=6.6 Hz, 2H),1.63-1.75 (m, 4H), 1.55-1.62 (m, 2H), 1.54-1.45 (m, 2H), 1.44-1.33 (m,2H), 1.30-1.18 (m, 2H).

LC-MS: t_(R)=2.227 min (method 13), m/z=344.2 [M+H]⁺.

Example 69

7-(4-methoxybenzyl)-6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (150 mg, 0.79 mmol, 1 eq) and3-methyltetrahydro-2H-pyran-4-carboxylic acid (125 mg, 870 μmol, 1.1 eq)in DCM (5 mL) was added HATU (451 mg, 1.19 mmol, 1.5 eq) and DIPEA (204mg, 1.58 mmol, 276 μL, 2 eq). The mixture was stirred at 25° C. for 18hours. The mixture was concentrated. The crude product was purified byflash chromatography with petroleum ether:ethyl acetate=3:1 2:1.N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyltetrahydro-2H-pyran-4-carboxamide(220 mg, 780 μmol, 99% yield) was obtained.

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyltetrahydro-2H-pyran-4-carboxamide(220 mg, 788 μmol, 1 eq) in dioxane (8 mL) was added POCl₃ (242 mg, 1.58mmol, 146 μL, 2 eq). The mixture was stirred at 80° C. for 2 hours. Themixture was concentrated.6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8-ol(223 mg, hydrochloride salt) was used in the next step without furtherpurification.

Step 3: To a solution of6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8-01(170 mg, 0.6 mmol) in DMF (5 mL) was added Cs₂CO₃ (586 mg, 1.80 mmol, 3eq) and 1-(chloromethyl)-4-methoxybenzene (113 mg, 719 μmol, 98 μL, 1.20eq). The mixture was stirred at 60° C. for 18 hours. The reactionmixture was filtered, and the filtrate was concentrated. The crudemixture was purified by preparative LC-MS, and then by preparative TLCwith ethyl acetate as eluent.7-(4-methoxybenzyl)-6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(76 mg, 207 μmol, 35% yield) was obtained.

¹H NMR, a mixture of diastereoisomers (CDCl₃400 MHz): δ 7.96-7.94 (m,1H), 7.18 (d, J=8.0 Hz, 2H), 6.86 (d, J=8.0 Hz, 2H), 6.76 (s, 0.73H),6.71 (s, 0.28H), 5.22-5.12 (m, 2H), 4.17-4.01 (m, 2H), 3.79 (s, 3H),3.55-3.49 (m, 1H), 3.19-3.14 (m, 1H), 2.66-2.64 (m, 1H), 2.36-2.33 (m,1H), 2.21 (s, 3H), 2.13-2.10 (m, 1H), 1.78-1.61 (m, 1H), 0.87 (d, J=7.2Hz, 1H), 0.71 (d, J=6.8 Hz, 2H).

LC-MS: t_(R)=2.370 min (method 11), m/z=368.1 [M+H]⁺.

Example 70

racemic7-(4-methoxybenzyl)-6-methyl-3-((1R,2R,4S)-2-methyl-7-oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (150 mg, 791 μmol, 1 eq) in dry DCM (5 mL) was addedtriethylamine (240 mg, 2.37 mmol, 329 μL, 3 eq), racemic(1R,2S,4S)-2-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (124mg, 791 μmol, 1 eq) and HATU (361 mg, 949 μmol, 1.20 eq). The mixturewas stirred at 15° C. for 16 hours. H₂O (5 mL) was added and the mixturewas extracted with DCM (20 mL×2). The combined organic layer was washedwith H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (0%˜50% ethyl acetate in petroleum ether) to give racemic(1R,2S,4S)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxamide(200 mg, 87% yield).

Step 2: To a solution of racemic(1R,2S,4S)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methyl-7-oxabicyclo[2.2.1]heptane-2-carboxamide(150 mg, 515 μmol, 1 eq) in dry dioxane (5 mL) was added POCl₃ (158 mg,1.03 mmol, 96 μL, 2 eq). The mixture was heated at 80° C. for 2 hours.The mixture was cooled to 15° C. and poured into water (5 mL). Themixture was adjusted to pH 8 by saturated aqueous NaHCO₃ and extractedwith DCM (20 mL×2). The combined organics were washed with H₂O (20 mL),brine (20 mL), dried over Na₂SO₄, filtered and concentrated to giveracemic6-methyl-3-((1R,2R,4S)-2-methyl-7-oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8-ol(120 mg).

Step 3: To a solution of racemic6-methyl-3-((1R,2R,4S)-2-methyl-7-oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8-ol(100 mg, 386 μmol, 1 eq) in dry DMF (5 mL) was added1-(chloromethyl)-4-methoxy-benzene (72 mg, 463 μmol, 63 μL, 1.20 eq) andCs₂CO₃ (251 mg, 771 μmol, 2 eq). The mixture was heated at 60° C. for 2hours. The mixture was concentrated. DCM (20 mL) and H₂O (10 mL) wasadded. The mixture was extracted with DCM (20 mL). The organic layer waswashed with H₂O (20 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by preparative LC-MS to give racemic7-(4-methoxybenzyl)-6-methyl-3-((1R,2R,4S)-2-methyl-7-oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 27% yield).

¹H NMR (CDCl₃ 400 MHz): b 7.87 (s, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.84 (d,J=8.8 Hz, 2H), 6.69 (s, 1H), 5.23-5.07 (m, 2H), 4.67 (d, J=4.8 Hz, 2H),3.78 (s, 3H), 2.71 (d, J=12.0 Hz, 1H), 2.20 (s, 3H), 1.90-1.86 (m, 1H),1.70-1.66 (m, 2H), 1.57 (s, 3H), 1.39-1.37 (m, 1H), 1.25-1.22 (m, 1H).

LC-MS: t_(R)=2.228 min (method 13), m/z=380.2 [M+H]⁺.

Example 71

(S)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (300 mg, 1.58 mmol) and (S)-2-phenylpropanoic acid (261mg, 1.74 mmol, 237 μL, 1.10 eq) in DCM (10 mL) was added triethylamine(400 mg, 3.95 mmol, 548 μL, 2.50 eq) and HATU (901 mg, 2.37 mmol, 1.50eq). The mixture was stirred at 15° C. for 12 hours. Water (50 mL) wasadded to the solution. The mixture was extracted with DCM (50 mL×2). Thecombined organic layers were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by flash silica gel chromatography (Eluent of 0˜20% Ethylacetate/petroleum ether).(S)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-phenylpropanamide (450mg, 1.56 mmol, 99% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.81 (s, 1H), 7.24-7.37 (m, 5H), 6.74 (s, 1H),4.37-4.52 (m, 2H), 3.92 (s, 3H), 3.67 (q, J=7.1 Hz, 1H), 2.40 (s, 3H),1.56 (d, J=7.2 Hz, 3H).

Step 2: To a solution of(S)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-phenylpropanamide (450mg, 1.58 mmol, 1 eq) in dioxane (10 mL) was added POCl₃ (485 mg, 3.16mmol, 294 μL, 2 eq). The mixture was stirred at 90° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure to removedioxane. The residue was quenched by addition H₂O (50 mL) at 0° C.,basified by addition saturated aqueous NaHCO₃ (10 mL) and then extractedwith EtOAc (50 mL×2). The combined organic layers were washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash silica gel chromatography(Eluent of 0˜100% Ethyl acetate/petroleum ether).(S)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8-ol (128 mg, 505μmol, 32% yield).

Step 3: To a solution of(S)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8-ol (128 mg, 505μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (95 mg, 0.61 mmol, 83μL, 1.20 eq) in DMF (10 mL) was added Cs₂CO₃ (329.29 mg, 1.01 mmol, 2eq). The mixture was stirred at 60° C. for 3 hours. The reaction mixturewas concentrated under reduced pressure. The residue was purified bypreparative LC-MS was further purified by SFC.(S)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one(76.40 mg, 203 μmol, 40% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.98 (s, 1H), 7.17-7.31 (m, 5H), 7.12 (d,J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.46 (s, 1H), 5.10 (dd, J=15.6Hz, 2H), 4.26 (q, J=7.2 Hz, 1H), 3.76 (s, 3H), 2.05 (s, 3H), 1.81 (d,J=7.6 Hz, 3H).

LC-MS: t_(R)=2.218 min (method 17), m/z=374.2 [M+H]⁺. SFC: t_(R)=1.641min, ee %>99%, [α]_(D) ²⁰=−51.4 (c=0.11, MeOH).

Example 72

(R)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (200 mg, 1.05 mmol, 1 eq) and (R)-2-phenylpropanoic acid(190 mg, 1.27 mmol, 173 μL, 1.20 eq) in DCM (10 mL) was addedtriethylamine (267 mg, 2.64 mmol, 365 μL, 2.50 eq) and HATU (602 mg,1.58 mmol, 1.50 eq). The mixture was stirred at 15° C. for 12 hours.Water (50 mL) was added to the solution. The mixture was extracted withDCM (50 mL×2). The combined organic layers were washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash silica gel chromatography(Eluent of 020% Ethyl acetate/petroleum ether).(R)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-phenylpropanamide (300mg, 1.02 mmol, 97% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 57.81 (s, 1H), 7.24-7.37 (m, 5H), 6.75 (s,1H), 4.37-4.52 (m, 2H), 3.91 (s, 3H), 3.67 (q, J=7.2 Hz, 1H), 2.40 (s,3H), 1.56 (d, J=7.2 Hz, 3H).

Step 2: To a solution of(R)—N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-phenylpropanamide (450mg, 1.58 mmol, 1 eq) in dioxane (10 mL) was added POCl₃ (727 mg, 4.74mmol, 440 μL, 3 eq). The mixture was stirred at 90° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure to removedioxane. The residue was quenched by addition of H₂O (50 mL) at 0° C.,basified by addition saturated aqueous NaHCO₃ (10 mL) and then extractedwith EtOAc (50 mL×2). The combined organic layers were washed with brine(50 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by flash silica gel chromatography(Eluent of 0˜100% Ethyl acetate/petroleum ether).(R)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8-ol (150 mg, 592μmol, 37% yield) was obtained.

Step 3: To a solution of(R)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8-ol (100 mg, 395μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (74 mg, 474 μmol, 65μL, 1.20 eq) in DMF (5 mL) was added Cs₂CO₃ (257 mg, 790 μmol, 2 eq).The mixture was stirred at 60° C. for 3 hours. The reaction mixture wasconcentrated under reduced pressure. The residue was purified bypreparative LC-MS.(R)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one(140 mg, 95% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.98 (s, 1H), 7.17-7.32 (m, 5H), 7.12 (d,J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 6.46 (s, 1H), 5.10 (dd, J=16.0Hz, 2H), 4.26 (q, J=7.2 Hz, 1H), 3.76 (s, 3H), 2.05 (s, 3H), 1.81 (d,J=6.8 Hz, 3H).

LC-MS: t_(R)=2.184 min (method 18), m/z=374.1 [M+H]⁺. SFC: t_(R)=1.324min, ee %=97.8%, [α]_(D) ²⁰=+50.7 (c=0.11, MeOH).

Example 73

3-(1,4-dimethylpiperidin-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (150 mg, 791 μmol) in DCM (5 mL) was added1,4-dimethylpiperidine-4-carboxylic acid hydrochloride (169 mg, 870μmol, 1.10 eq, HCl), triethylamine (240 mg, 2.37 mmol, 329 μL, 3 eq) andHATU (361 mg, 949 μmol, 1.20 eq). The mixture was stirred at 15° C. for16 hours. The mixture was concentrated. The residue was purified bypreparative TLC (DCM/MeOH=10/1) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-1,4-dimethylpiperidine-4-carboxamide(150 mg, 65% yield).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-1,4-dimethylpiperidine-4-carboxamide(100 mg, 342 μmol, 1 eq) in dry dioxane (5 mL) was added POCl₃ (105 mg,684 μmol, 64 μL, 2 eq). The mixture was heated at 80° C. for 4 hours.The mixture was cooled to 15° C. and poured into water (5 mL). Themixture was adjusted to pH 8 by saturated aqueous NaHCO₃ andconcentrated. 10% MeOH in DCM (20 mL) was added to the residue andfiltered, the filtrate was concentrated to give3-(1,4-dimethylpiperidin-4-yl)-6-methylimidazo[1,5-a]pyrazin-8-ol (90mg).

Step 3: To a solution of3-(1,4-dimethylpiperidin-4-yl)-6-methylimidazo[1,5-a]pyrazin-8-ol (60mg, 230 μmol, 1 eq) in DMF (2 mL) was added1-(chloromethyl)-4-methoxybenzene (54 mg, 346 μmol, 47 μL, 1.50 eq) andCs₂CO₃ (150 mg, 461 μmol, 2 eq). The mixture was heated at 60° C. for 2hours. The mixture was concentrated. DCM (20 mL) and H₂O (10 mL) wereadded. The mixture was extracted with DCM (20 mL). The organic layer waswashed with H₂O (20 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by preparative LC-MS to give3-(1,4-dimethylpiperidin-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(20 mg, 23% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.17 (d, J=8.8 Hz, 2H), 6.94 (s,1H), 6.84 (d, J=8.8 Hz, 2H), 5.15 (s, 2H), 3.78 (s, 3H), 2.58-2.56 (m,2H), 2.49-2.45 (m, 2H), 2.38-2.35 (m, 2H), 2.25 (s, 3H), 2.19 (s, 3H),1.86-1.80 (m, 2H), 1.42 (s, 3H).

LC-MS: t_(R)=1.747 min (method 13), m/z=381.2 [M+H]⁺.

Example 74

3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (200 mg, 1.05 mmol) and6-chloro-2,3-dihydro-1H-indene-1-carboxylic acid (206 mg, 1.05 mmol, 1eq) in DCM (5 mL) was added HATU (479 mg, 1.26 mmol, 1.20 eq) and DIPEA(407 mg, 3.15 mmol, 550 μL, 3 eq). The mixture was stirred at 18° C. for16 hours. The mixture washed with H₂O (20 mL) and extracted with DCM (20mL×3). The combined organic was dried over Na₂SO₄ and concentrated undervacuum.6-chloro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide(312 mg, 864 μmol, 82% yield) was obtained.

Step 2: To a solution of6-chloro-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,3-dihydro-1H-indene-1-carboxamide(0.262 g, 1 eq) in dioxane (10 mL) was added POCl₃ (363 mg, 2.37 mmol,220 μL, 3 eq). The mixture was stirred at 80° C. for 3 hours. Themixture was quenched by H₂O (20 mL) and adjusted pH>7 by saturatedaqueous NaHCO₃. The mixture was extracted with DCM (25 mL×3). Thecombined organic was dried over Na₂SO₄ and concentrated under vacuum.3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(236 mg) was obtained and directly used to next step.

Step 3: To a solution of3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(236 mg, 787 μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (148 mg,945 μmol, 1.20 eq) in DMF (12 mL) was added Cs₂CO₃ (513 mg, 1.57 mmol, 2eq). The mixture was stirred at 60° C. for 2.5 hours. The mixture wasconcentrated under vacuum. The residue was quenched with H₂O (15 mL) andextracted with DCM (20 mL×3). The combined organic phases were driedover Na₂SO₄ and concentrated under vacuum. The residue was purified bypreparative HPLC.3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(99 mg, 237 μmol, 30% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.93 (s, 1H), 7.30-7.18 (m, 4H), 6.98 (s, 1H),6.88 (d, J=8.8 HZ, 2H), 6.64 (s, 1H), 5.18 (s, 2H), 4.71 (t, J=8.4 HZ1H), 3.79 (s, 3H), 3.16-3.13 (m, 1H), 3.05-2.96 (m, 1H), 2.64-2.61 (m,1H), 2.52-2.49 (m, 1H), 2.17 (s, 3H).

LC-MS: t_(R)=2.358 min (method 17), m/z=420.1 [M+H]⁺.

Example 75

7-(4-methoxybenzyl)-6-methyl-3-(3-methyl-5-oxopyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of ethyl 3-methyl-5-oxopyrrolidine-3-carboxylate(200 mg, 1.17 mmol, 1 eq) in THF (4 mL) and H₂O (2 mL) was addedLiOH—H₂O (147.06 mg, 3.50 mmol, 3 eq). The mixture was stirred at 20° C.for 16 hours. The mixture was acidified to pH=2 by 1 M HCl and extractedwith ethyl acetate (20 mL×3). The combined organic layers were washedwith H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give 3-methyl-5-oxopyrrolidine-3-carboxylic acid (100mg, 60% yield).

Step 2: To a cooled (0° C.) solution of3-methyl-5-oxopyrrolidine-3-carboxylic acid (100 mg, 0.7 mmol, 1 eq) inDCM (2 mL) was added oxalyl dichloride (98 mg, 768 μmol, 67 μL, 1.10 eq)and one drop of dry DMF was added. The mixture was stirred at 20° C. for1 hour. The colorless solution of 3-methyl-5-oxopyrrolidine-3-carbonylchloride (112.89 mg) in DCM (2 mL) was directly used for the next step.

Step 3: To a cooled (0° C.) solution of(3-methoxy-5-methylpyrazin-2-yl)methanamine (120 mg, 633 μmol, 1 eq,HCl) in dry DCM (3 mL) was added triethylamine (192 mg, 1.90 mmol, 263μL, 3 eq) and a solution of 3-methyl-5-oxopyrrolidine-3-carbonylchloride (112 mg, 696 μmol, 1.10 eq) in dry DCM (2 mL) dropwise. Themixture was stirred at 20° C. for 1 hour. H₂O (5 mL) was added and themixture was extracted with DCM (20 mL×2). The combined organic layer waswashed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by preparative TLC(DCM/MeOH=10/1) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyl-5-oxopyrrolidine-3-carboxamide(75 mg, 42% yield).

Step 4: A solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-3-methyl-5-oxopyrrolidine-3-carboxamide(100 mg, 359 μmol, 1 eq) in Eaton's reagent (7.7 wt % phosphoruspentoxide solution in methanesulfonic acid) (2 mL) was heated at 60° C.for 16 hours. The mixture was cooled to 15° C. and poured into ice (5g). The mixture was adjusted to pH=8 by 7 M NH₃/MeOH and concentrated.10% MeOH in DCM (20 mL) was added to the residue and filtered, thefiltrate was concentrated to give4-(8-hydroxy-6-methylimidazo[1,5-a]pyrazin-3-yl)-4-methylpyrrolidin-2-one(100 mg).

Step 5: To a solution of4-(8-hydroxy-6-methylimidazo[1,5-a]pyrazin-3-yl)-4-methylpyrrolidin-2-one(100 mg, 406 μmol, 1 eq) in DMF (5 mL) was added1-(chloromethyl)-4-methoxybenzene (76 mg, 487 μmol, 66 μL, 1.20 eq) andCs₂CO₃ (265 mg, 812 μmol, 2 eq). The mixture was heated at 60° C. for 2h. The mixture was concentrated. DCM (20 mL) and H₂O (10 mL) was added.The mixture was extracted with DCM (20 mL). The organic layers werewashed with H₂O (20 mL), dried over Na₂SO₄, filtered and concentrated.The mixture was purified by preparative HPLC to give7-(4-methoxybenzyl)-6-methyl-3-(3-methyl-5-oxopyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(40 mg, 27% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.87 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.84 (d,J=8.4 Hz, 2H), 6.65 (s, 1H), 5.93 (brs, 1H), 5.16 (s, 2H), 4.25 (d,J=9.6 Hz, 1H), 3.77 (s, 3H), 3.53 (d, J=10.4 Hz, 1H), 3.00 (d, J=16.8Hz, 1H), 2.57 (d, J=16.4 Hz, 1H), 2.20 (s, 3H), 1.63 (s, 3H).

LC-MS: t_(R)=1.764 min (method 11), m/z=367.1 [M+H]⁺.

Example 76

3-(1-methoxy-2-methylpropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of 3-methoxy-2,2-dimethylpropanoic acid (115 mg,870 μmol, 1 eq) in DCM (5 mL) was added oxalyl dichloride (121 mg, 957μmol, 84 μL, 1.10 eq) at 0° C., followed by one drop of DMF. The mixturewas stirred at 20° C. for 1 hour. The mixture was directly used to nextstep.

Step 2: To a solution of 3-methoxy-2,2-dimethylpropanoyl chloride (150mg, 791 μmol, 1 eq, HCl) and triethylamine (120 mg, 1.19 mmol, 164 μL,1.50 eq) in DCM (10 mL) was added(3-methoxy-5-methylpyrazin-2-yl)methanamine (131 mg, 870 μmol, 1.10 eq)in DCM (5 mL). The mixture was stirred at 20° C. for 1 hour. The mixturewas quenched with H₂O (20 mL) and extracted with DCM (15 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated undervacuum.3-methoxy-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,2-dimethylpropanamide(142 mg, 522 μmol, 66% yield) was obtained.

Step 3: To a solution of3-methoxy-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,2-dimethylpropanamide(102 mg, 382 μmol, 1 eq) in dioxane (5 mL) was added POCl₃ (117 mg, 763μmol, 71 μL, 2 eq). The mixture was stirred at 80° C. for 2 hours. Themixture was quenched with water (20 mL) and extracted with DCM (20mL×3). The combined organic layers were dried with Na₂SO₄ andconcentrated under vacuum.3-(1-methoxy-2-methylpropan-2-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(45 mg, 191 μmol, 50% yield) was obtained.

Step 4: To a solution of3-(1-methoxy-2-methylpropan-2-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(62 mg, 264 μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (49.52 mg,316 μmol, 43.06 μL, 1.20 eq) in DMF (5 mL) was added Cs₂CO₃ (171.72 mg,527 μmol, 2 eq). The mixture was stirred at 60° C. for 3 hours. Themixture washed with H₂O (20 mL) and extracted with DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by preparative HPLC.3-(1-methoxy-2-methylpropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(25.15 mg, 71 μmol, 27% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.91 (s, 1H), 7.20-7.17 (m, 3H), 6.86 (d,J=8.4 Hz, 2H), 5.15 (s, 2H), 3.79 (s, 3H), 3.59 (s, 2H), 3.35 (s, 3H),2.18 (s, 3H), 1.52 (s, 6H).

LC-MS: t_(R)=2.050 min (method 13), m/z=356.1 [M+H]⁺.

Example 77

3-isopropyl-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a cold (0° C.) solution of(3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (150 mg, 791μmol), Et₃N (176 mg, 1.74 mmol, 241 μL, 2.20 eq) in anhydrous DCM (5 mL)was added isobutyryl chloride (93 mg, 870 μmol, 91 μL, 1.10 eq). Thesolution was stirred at 0° C. for 0.5 h. The mixture was diluted withwater (20 mL), extracted with DCM (20 mL×2). The organic layer waswashed with brine (20 ml), dried over Na₂SO₄ and concentrated in vacuo.N-((3-methoxy-5-methylpyrazin-2-yl)methyl)isobutyramide (160 mg, 717μmol, 91% yield) was obtained.

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)isobutyramide (160 mg, 717μmol, 1 eq) in dioxane (5 mL) was added POCl₃ (220 mg, 1.43 mmol, 133μL, 2 eq). The mixture was stirred at 90° C. 2 hours. The mixture wasconcentrated in vacuo.3-isopropyl-8-methoxy-6-methylimidazo[1,5-a]pyrazine (130 mg, 633 μmol,88% yield) was obtained.

Step 3: A solution of3-isopropyl-8-methoxy-6-methylimidazo[1,5-a]pyrazine (130 mg, 633 μmol,1 eq) in 2M HCl(aq) (4 mL) and dioxane (8 mL) was stirred at 90° C. for2 hours. The mixture was concentrated in vacuo. The residue was purifiedby silica gel chromatography (DCM:MeOH=10:1).3-isopropyl-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (120 mg, 628 μmol,99% yield) was obtained.

Step 4: To a solution of3-isopropyl-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (120 mg, 628 μmol, 1eq) in DMF (8 mL) was added 1-(chloromethyl)-4-methoxy-benzene (118 mg,753 μmol, 103 μL, 1.20 eq) and Cs₂CO₃ (307 mg, 941 μmol, 1.50 eq). Themixture was stirred at 60° C. for 16 hours. The mixture was filtered.The filtrate was purified by pre-HPLC (base).3-isopropyl-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(90 mg, 287 μmol, 46% yield) was obtained.

¹H NMR (CDCl₃400 MHz): δ 7.90 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.85 (d,J=8.4 Hz, 1H), 6.71 (s, 1H), 5.16 (s, 2H), 3.78 (s, 2H), 3.18-3.11 (m,1H), 2.19 (s, 3H), 1.41-1.79 (d, J=7.2 Hz, 6H).

LC-MS: t_(R)=1.92 min (method 13), m/z=312.1 [M+H]⁺.

Example 78

6-methyl-7-((2-methylthiazol-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Into a vial was added6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (30mg, 0.13 mmol), cesium carbonate (84 mg, 0.26 mmol),4-(chloromethyl)-2-methylthiazole (23 mg, 0.15 mmol) and sodium iodide(23 mg, 0.15 mmol) in DMF (2 mL). The reaction was heated to 70° C., andstirred over night. The mixture was filtered and evaporated andsubsequently chromatographed on silicagel to obtain the crude product.Final purification on preparative LC-MS afforded6-methyl-7-((2-methylthiazol-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(3.9 mg, 0.013 mmol) in 10% yield.

¹H NMR (600 MHz, DMSO-d₆) b 8.17 (s, 1H), 7.63 (m, 1H), 7.30 (m, 1H),5.17 (s, 2H), 3.99 (t, J=3.3 Hz, 1H), 3.97 (t, J=3.1 Hz, 1H), 3.49 (m,3H), 2.61 (s, 3H), 2.36 (d, J=1.2 Hz, 3H), 1.83 (m, 4H).

LC-MS: t_(R)=0.39 min (method 5), m/z=344.9 [M+H]⁺.

Example 79

6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiophen-3-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one

Into a vial was added6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (30mg, 0.129 mmol), cesium carbonate (84 mg, 0.26 mmol),3-(chloromethyl)thiophene (20 mg, 0.15 mmol) and sodium iodide (23 mg,0.15 mmol) in DMF (2 mL). The reaction was heated to 70° C., and stirredover night. The mixture was filtered and evaporated and subsequentlychromatographed on silicagel to obtain the crude product. Finalpurification on preparative LC-MS afforded6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiophen-3-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one(10 mg, 0.0324 mmol) in 25% yield.

¹H NMR (600 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.66 (m, 1H), 7.53 (dd, J=5.0,2.9 Hz, 1H), 7.35 (dq, J=2.2, 1.0 Hz, 1H), 7.05 (dd, J=5.0, 1.3 Hz, 1H),5.17 (s, 2H), 3.98 (dt, J=11.4, 3.4 Hz, 2H), 3.49 (m, 3H), 2.26 (d,J=1.2 Hz, 3H), 1.84 (m, 4H).

LC-MS: t_(R)=0.45 min (method 5), m/z=329.9 [M+H]⁺.

Example 80

6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiazol-4-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one

Into a vial was added6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (30mg, 0.129 mmol), cesium carbonate (147 mg, 0.450 mmol),4-(chloromethyl)thiazole hydrochloride (26 mg, 0.15 mmol) and sodiumiodide (23 mg, 0.15 mmol) in DMF (2 mL). The reaction was heated to 70°C., and stirred over night. The mixture was filtered and evaporated andsubsequently chromatographed on silicagel to obtain the crude product.Final purification on preparative LC-MS afforded6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiazol-4-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one(7 mg, 0.0153 mmol) in 12% yield.

¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (d, J=1.9 Hz, 1H), 8.12 (s, 1H), 7.63(m, 1H), 7.57 (dd, J=1.9, 0.9 Hz, 1H), 5.27 (s, 2H), 3.97 (dt, J=11.3,3.3 Hz, 2H), 3.48 (m, 3H), 2.36 (d, J=1.2 Hz, 3H), 1.84 (m, 4H).

LC-MS: t_(R)=0.34 min (method 5), m/z=331.0 [M+H]⁺.

Example 81

7-((3,5-dimethylisoxazol-4-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Into a vial was added6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (25mg, 0.107 mmol), cesium carbonate (70 mg, 0.21 mmol),4-(chloromethyl)-3,5-dimethylisoxazole (19 mg, 0.129 mmol) and sodiumiodide (19 mg, 0.129 mmol) in DMF (1.6 mL). The reaction was heated to70° C., and stirred over night. The mixture was filtered and evaporatedand subsequently chromatographed on silicagel to obtain the crudeproduct. Final purification on preparative LC-MS afforded7-((3,5-dimethylisoxazol-4-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(11 mg, 0.024 mmol) in 23% yield.

¹H NMR (600 MHz, DMSO-d₆) δ 8.11 (s, 1H), 7.63 (m, 1H), 5.00 (s, 2H),3.97 (dt, J=11.3, 3.3 Hz, 2H), 3.46 (m, 3H), 2.27 (s, 3H), 2.24 (d,J=1.2 Hz, 3H), 2.08 (s, 3H), 1.82 (dd, J=7.8, 3.5 Hz, 4H).

LC-MS: t_(R)=0.38 min (method 5), m/z=343.0 [M+H]⁺.

Example 82

6-methyl-7-((5-methylisoxazol-3-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Into a vial was added6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (25mg, 0.107 mmol), cesium carbonate (70 mg, 0.21 mmol),3-(chloromethyl)-5-methylisoxazole (34 mg, 0.13 mmol, 50%) and sodiumiodide (19 mg, 0.13 mmol) in DMF (1.6 mL). The reaction was heated to70° C., and stirred over night. The mixture was filtered and evaporatedand subsequently chromatographed on silicagel to obtain the crudeproduct.

Final purification on preparative LC-MS afforded6-methyl-7-((5-methylisoxazol-3-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(9 mg, 0.0194 mmol) in 18% yield.

¹H NMR (600 MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.60 (m, 1H), 6.19 (q, J=0.8Hz, 1H), 5.18 (s, 2H), 3.97 (dt, J=11.3, 3.4 Hz, 2H), 3.45 (m, 3H), 2.37(d, J=0.9 Hz, 3H), 2.27 (d, J=1.2 Hz, 3H), 1.86-1.79 (m, 4H).

LC-MS: t_(R)=0.38 min (method 5), m/z=328.9 [M+H]⁺.

Example 83

6-methyl-7-((3-methylisoxazol-5-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Into a vial was added6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (25mg, 0.107 mmol), cesium carbonate (70 mg, 0.21 mmol),5-(chloromethyl)-3-methylisoxazole (17 mg, 0.13 mmol) and sodium iodide(19 mg, 0.13 mmol) in DMF (1.6 mL). The reaction was heated to 70° C.,and stirred over night. The mixture was filtered and evaporated andsubsequently chromatographed on silicagel to obtain the crude product.Final purification on preparative LC-MS afforded6-methyl-7-((3-methylisoxazol-5-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(14 mg, 0.0313 mmol) in 29% yield.

¹H NMR (600 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.70 (m, 1H), 6.31 (s, 1H),5.29 (m, 2H), 3.98 (dt, J=11.4, 3.5 Hz, 2H), 3.49 (m, 3H), 2.32 (d,J=1.2 Hz, 3H), 2.19 (s, 3H), 1.85 (m, 4H). LC-MS: t_(R)=0.37 min (method5), m/z=328.9 [M+H]⁺.

Example 84

3-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (200 mg, 1.05 mmol, 1 eq) and2,6-dimethyltetrahydro-2H-pyran-4-carboxylic acid (167 mg, 1.05 mmol, 1eq) in DCM (10 mL) was added HATU (481 mg, 1.27 mmol, 1.20 eq) and DIPEA(409 mg, 3.16 mmol, 552 μL, 3 eq). The mixture was stirred at 18° C. for16 hours. The mixture washed with H₂O (20 mL) and extracted with DCM (20mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum.N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,6-dimethyltetrahydro-2H-pyran-4-carboxamide(300 mg, 0.95 mmol, 90% yield) was obtained.

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2,6-dimethyltetrahydro-2H-pyran-4-carboxamide(280 mg, 954 μmol, 1 eq) in dioxane (10 mL) was added POCl₃ (293 mg,1.91 mmol, 177 μL, 2 eq). The mixture was stirred at 80° C. for 2 hours.The mixture washed with H₂O (20 mL) and extracted with DCM (20 mL×3).The combined organic layers were dried over Na₂SO₄ and concentratedunder vacuum.3-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(249 mg) was obtained.

Step 3: To a solution of3-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 765 μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (156 mg,995 μmol, 135 μL, 1.30 eq) in DMF (10 mL) was added Cs₂CO₃ (500 mg, 1.53mmol, 2 eq). The mixture was stirred at 60° C. for 4 hours. The mixturewas concentrated under vacuum. The mixture was washed with H₂O (20 mL)and extracted with DCM (15 mL×3). The combined organic layers werewashed with H₂O (40 mL×3), brine, dried over Na₂SO₄ and concentratedunder vacuum. The residue was purified by preparative LC-MS to give3-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(48 mg, 126 μmol, 16% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.91 (s, 1H), 7.16 (d, J=8.4 HZ, 2H), 6.85 (d,J=8.4 HZ, 2H), 6.73 (s, 2H), 5.17 (s, 2H), 3.79 (s, 3H), 3.67-3.63 (m,2H), 3.14-3.08 (m, 1H), 2.21 (s, 3H), 1.90-1.87 (m, 3H), 1.75-1.62 (m,2H), 1.28 (d, J=6.0 HZ, 6H).

LC-MS: t_(R)=2.133 min (method 17), m/z=382.1 [M+H]⁺.

Example 85

7-(cyclohexylmethyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of 3-bromo-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(1 g, 4.39 mmol, 1 eq) and Cs₂CO₃ (2.86 g, 8.78 mmol, 2 eq) in DMF (20mL) was added (bromomethyl)cyclohexane (1.55 g, 8.78 mmol, 1.22 mL, 2eq). The mixture was stirred at 60° C. for 18 hour. The reaction mixturewas filtered and the filtrate was concentrated. The crude mixture waspurified by flash chromatography with petroleum ether:ethylacetate=5:1˜3:1.3-bromo-7-(cyclohexylmethyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (1g, 3.02 mmol, 69% yield) was obtained.

¹H NMR (CDCl₃, 400 MHz): δ7.86 (s, 1H), 6.80 (s, 1H), 3.79 (d, J=7.2 Hz,2H), 2.29 (s, 3H), 1.75-1.66 (m, 6H), 1.22-1.04 (m, 5H).

LC-MS: t_(R)=0.791 min (method 15), m/z=325.9 [M+H]⁺.

Step 2: To a solution of3-bromo-7-(cyclohexylmethyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 617 μmol, 1 eq) and(E)-4,4,5,5-tetramethyl-2-(prop-1-en-1-yl)-1,3,2-dioxaborolane (155 mg,925 μmol, 1.50 eq) in dioxane (4 mL) and H₂O (1 mL) was addedPd(dppf)Cl2 (90 mg, 123 μmol, 0.20 eq) and Cs₂CO₃ (402 mg, 1.23 mmol, 2eq) under a N₂ atmosphere. The mixture was stirred at 90° C. for 2 hoursunder microwave conditions. Water (50 mL) was added and the mixture wasextracted with EtOAc (50 mL×3), the combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄ and concentrated. The crudemixture was purified by flash chromatography with petroleum ether:ethylacetate=1:1.(E)-7-(cyclohexylmethyl)-6-methyl-3-(prop-1-en-1-yl)imidazo[1,5-a]pyrazin-8(7H)-one(150 mg, 504.59 μmol, 82% yield) was obtained.

Step 3: To a solution of(E)-7-(cyclohexylmethyl)-6-methyl-3-(prop-1-en-1-yl)imidazo[1,5-a]pyrazin-8(7H)-one(150 mg, 526 μmol, 1 eq) in EtOAc (30 mL) was added Pd—C(10%, 40 mg,wet) under N₂. The suspension was degassed under vacuum and purged withH₂ several times. The mixture was stirred under H₂ (15 psi) at 25° C.for 18 hours. The mixture was filtered and the residue was washed withEtOAc (20 mL×2). The combined organic layers were concentrated. Theresidue was purified by preparative LC-MS to give7-(cyclohexylmethyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one(95.5 mg, 321 μmol, 61% yield).

¹H NMR (400 MHz): δ 7.83 (s, 1H), 6.66 (s, 1H), 3.78 (d, J=7.2 Hz, 2H),2.81 (t, J=7.6 Hz, 2H), 2.26 (s, 3H), 1.86-1.84 (m, 2H), 1.76-1.67 (m,6H), 1.19-1.17 (m, 3H), 1.05-1.01 (m, 5H).

LC-MS: t_(R)=1.68 min (method 17), m/z=288.3 [M+H]⁺.

Example 86

3-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

Step 1: NaH (2.64 g, 66 mmol, 60% in mineral oil, 2.20 eq) was added to2-hydroxy-2-methylpropanoic acid (3.12 g, 30 mmol, 1 eq) in DMF (30 mL)at 0° C. The mixture was stirred a t 20° C. for 30 mins.(bromomethyl)benzene (10.26 g, 60 mmol, 7.13 mL, 2 eq) was added to thereaction mixture at 20° C. and stirred at 20° C. for 16 hours. Themixture was quenched by H₂O (30 mL) and adjusted pH=7 by HCl (1 M, aq).The mixture was extracted with ethyl acetate (30 mL×3). The combinedorganic layers were washed by H₂O (20 mL) and brine. The residue wasdried over Na₂SO₄ and concentrated under vacuum. ¹H NMR showed thecompound was desired product. benzyl 2-(benzyloxy)-2-methylpropanoate(3.98 g, 14 mmol, 47% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.40-7.32 (m, 10H), 5.24 (s, 2H), 4.48 (s,2H), 1.58 (s, 6H).

Step 2: To a solution of benzyl 2-(benzyloxy)-2-methylpropanoate (2 g,7.03 mmol, 1 eq) in H₂O (20 mL), THF (20 mL) and MeOH (20 mL) was addedNaOH (1.12 g, 27.98 mmol, 3.98 eq). The mixture was stirred at 80° C.for 1 hour. The mixture was adjusted pH=2 by aq. HCl (1 M) and extractedwith DCM (10 mL×3). The combined organic layers were concentrated undervacuum. The residue was washed with aq. NaOH (1 M, 5 mL) and extractedwith DCM (15 mL×3). The aqueous solution was adjusted pH=2 by aq. HCl (1M, aq) and extracted with DCM (10 mL×3). The combined organic layerswere washed with H₂O (15 mL×2) and brine. The mixture was dried overNa₂SO₄ and concentrated under vacuum. 2-(benzyloxy)-2-methylpropanoicacid (1.36 g, 7 mmol, 100% yield) was obtained.

Step 3: To a solution of 2-(benzyloxy)-2-methylpropanoic acid (500 mg,2.64 mmol, 1 eq, HCl) in DCM (10 mL) was added DIPEA (1.02 g, 7.92 mmol,1.38 mL, 3 eq). The mixture was added(3-methoxy-5-methylpyrazin-2-yl)methanamine hydrochloride (513 mg, 2.64mmol, 1 eq) and HATU (1.20 g, 3.17 mmol, 1.20 eq). The mixture wasstirred at 18° C. for 16 hours. The mixture washed with H₂O (20 mL) andextracted with DCM (20 mL×3). The combined organic layers were driedover Na₂SO₄ and concentrated under vacuum.2-(benzyloxy)-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methylpropanamide(617 mg, 1.75 mmol, 66% yield) was obtained.

Step 4: To a solution of2-(benzyloxy)-N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-methylpropanamide(1.40 g, 4.25 mmol, 1 eq) in dioxane (20 mL) was added POCl₃ (1.30 g,8.50 mmol, 790 μL, 2 eq). The mixture was stirred at 80° C. for 2 hours.The mixture was quenched with H₂O (15 mL) and adjusted pH>7 by saturatedaqueous NaHCO₃. The mixture was extracted with DCM (20 mL×3). Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated under vacuum.3-(2-(benzyloxy)propan-2-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(375 mg, 1.26 mmol, 30% yield) was obtained.

Step 5: To a solution of3-(2-(benzyloxy)propan-2-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(264 mg, 888 μmol, 1 eq) in DMF (10 mL) was added Cs₂CO₃ (579 mg, 1.78mmol, 2 eq) and 1-(chloromethyl)-4-methoxybenzene (180.76 mg, 1.15 mmol,1578 μL, 1.30 eq). The mixture was stirred at 60° C. for 4 hours. Themixture was concentrated under vacuum. The mixture was washed with H₂O(25 mL) and extracted with DCM (20 mL). The combined organic layers weredried over Na₂SO₄ and concentrated under vacuum.3-(2-(benzyloxy)propan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(445 mg, 998 μmol, 64% yield) was obtained.

Step 6: To a solution of3-(2-(benzyloxy)propan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(345 mg, 826 μmol, 1 eq) in MeOH (60 mL) was added Pd/C (10%, wet) (40mg). The mixture was stirred at pressure of H₂ (30 psi). The mixture wasstirred at 18° C. for 8 hours. The mixture was filtered. The filteredsolution was concentrated under vacuum. The residue was purified by TLC(petroleum ether:ethyl acetate=1:1).3-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(98 mg, 292 μmol, 35% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.86 (s, 1H), 7.47 (s, 1H), 7.17 (d, J=12 Hz,2H), 6.85 (d, J=8.4 Hz, 2H), 5.17 (s, 2H), 3.79 (s, 3H), 2.216-2.192 (m,4H), 1.76 (s, 3H).

LC-MS: t_(R)=1.906 min (method 13), m/z=328.2 [M+H]⁺.

Example 87

3-(2-fluoropropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

To a solution of3-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(75 mg, 229.09 μmol, 1 eq) in DCM (10 ml) was added DAST (40.6 mg, 252μmol, 33 μL, 1.10 eq) at −78° C. The mixture was stirred at 18° C. for 2hours. The mixture was quenched with H₂O (10 mL) and extracted with DCM(15 mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified with TLC (petroleumether:ethyl acetate=1:1).3-(2-fluoropropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(68 mg, 206 μmol, 64% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.89 (s, 1H), 7.19-7.16 (m, 3H), 6.86 (d,J=8.4 Hz, 2H), 5.18 (s, 2H), 3.79 (s, 3H), 2.20 (s, 3H), 1.91 (s, 3H),1.86 (s, 3H).

LC-MS: t_(R)=1.906 min (method 13), m/z=328.2 [M+H]⁺.

Example 88

7-(4-methoxybenzyl)-6-methyl-3-(7-oxoazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (500 mg, 2.64 mmol, 1 eq) and 7-oxoazepane-4-carboxylicacid (456 mg, 2.90 mmol, 1.10 eq) in DCM (45 mL) was added HATU (1.20 g,3.17 mmol, 1.20 eq) and DIPEA (1.02 g, 7.92 mmol, 1.38 mL, 3 eq). Themixture was stirred at 18° C. for 16 hours. The mixture was quenchedwith H₂O (30 mL) and extracted with DCM (25 mL×3). The combined organiclayers were dried over Na₂SO₄ and concentrated under vacuum.N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-7-oxoazepane-4-carboxamide(493 mg, 1.58 mmol, 60% yield) was obtained.

Step 2:N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-7-oxoazepane-4-carboxamide(463 mg, 1.58 mmol, 1 eq) was added to Eaton's reagent (7.7 wt %phosphorus pentoxide solution in methanesulfonic acid) (3.04 g, 12.77mmol, 2 mL, 8.08 eq). The mixture was stirred at 60° C. for 7 hours. Themixture was added to ice (30 g). The mixture was adjusted pH>7 by NH₃(MeOH). The mixture was concentrated under vacuum. The residue waswashed with DCM:MeOH=10:1. The mixture was filtered. The filteredsolution was concentrated under vacuum.6-methyl-3-(7-oxoazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (45 mg,165.83 μmol, 11% yield) was obtained.

¹H NMR (MeOD 400 MHz): δ 7.77 (s, 1H), 7.23 (s, 2H), 3.49-3.39 (m, 3H),2.83-2.79 (m, 2H), 2.55-2.51 (m, 1H), 2.19 (s, 3H), 2.11-2.09 (m, 2H),1.93-1.86 (m, 2H).

Step 3: To a solution of6-methyl-3-(7-oxoazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one (45 mg, 173μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (32 mg, 207 μmol, 28μL, 1.20 eq) in DMF (3 mL) was added Cs₂CO₃ (113 mg, 346 μmol, 2 eq).The mixture was stirred at 60° C. for 2 hours. The mixture was washedwith H₂O (10 mL) and extracted with DCM (15 mL×3). The combined organiclayers were washed with water (30 mL×3), dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by TLC(DCM:MeOH=10:1).7-(4-methoxybenzyl)-6-methyl-3-(7-oxoazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(12 mg, 32 μmol, 18% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.89 (s, 1H), 7.15 (d, J=8.8 HZ, 2H), 6.84 (d,J=8.4 HZ, 2H), 6.70 (s, 1H), 6.36 (brs, 1H), 5.16 (s, 2H), 5.16 (s, 2H),3.77 (s, 3H), 3.62-3.49 (m, 1H), 3.42-3.30 (m, 1H), 3.20-3.10 (m, 1H),2.77-2.72 (m, 1H), 2.61-2.55 (m, 1H), 2.21 (s, 3H), 2.10-2.01 (m, 4H).

LC-MS: t_(R)=1.748 min (method 13), m/z=381.2 [M+H]⁺.

Example 89

7-(4-methoxybenzyl)-6-methyl-3-(5-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(200 mg, 1.05 mmol, 1 eq, HCl) and 5-methyltetrahydrofuran-3-carboxylicacid (137 mg, 1.05 mmol, 1 eq) in DCM (10 mL) was added HATU (481 mg,1.27 mmol, 1.20 eq) and DIPEA (409 mg, 3.16 mmol, 553 μL, 3 eq). Themixture was stirred at 18° C. for 16 hours. The mixture washed with H₂O(20 mL) and extracted with DCM (20 mL×3). The combined organic layerswere dried over Na₂SO₄ and concentrated under vacuum.N-((3-methoxy-5-methylpyrazin-2-yl)methyl)-5-methyltetrahydrofuran-3-carboxamide(211 mg, 795 μmol, 76% yield) was obtained.

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-5-methyltetrahydrofuran-3-carboxamide(191 mg, 720 μmol, 1 eq) in dioxane (5 mL) was added POCl₃ (221 mg, 1.44mmol, 134 μL, 2 eq). The mixture was stirred at 80° C. for 3 hours. Themixture washed with H₂O (20 mL) and extracted with DCM (20 mL×3). Thecombined organic layers were dried over Na₂SO₄ and concentrated undervacuum.6-methyl-3-(5-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(167 mg) was obtained.

Step 3: To a solution of6-methyl-3-(5-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(138 mg, 592 μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (120 mg,769 μmol, 1.30 eq) in DMF (10 mL) was added Cs₂CO₃ (386 mg, 1.18 mmol, 2eq). The mixture was stirred at 60° C. for 4 hours. The mixture wasconcentrated under vacuum. The mixture was washed with H₂O (20 mL) andextracted with DCM (15 mL×3). The combined organic layers were washedwith H₂O (40 mL×3, brine, dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by pre-HPLC(base).7-(4-methoxybenzyl)-6-methyl-3-(5-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(10 mg, 28 μmol, 5% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.90 (s, 1H), 7.16 (d, J=8.4 HZ, 2H),6.87-6.82 (m, 3H), 5.17 (s, 2H), 4.19-4.14 (m, 3H), 3.79-3.71 (m, 4H),2.54-2.47 (m, 1H), 2.20 (s, 3H), 2.04-1.96 (m, 1H), 1.40 (s, J=6.0 HZ,3H).

LC-MS: t_(R)=2.036 min (method 13), m/z=354.2 [M+H]⁺.

Example 90

7-(4-methoxybenzyl)-6-methyl-3-(1-(4-methylthiazol-2-yl)ethyl)imidazo[1,5-a]pyrazin-8(7H)-one

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanaminehydrochloride (150 mg, 791 μmol, 1 eq) in dry DMF (5 mL) was addedtriethylamine (240 mg, 2.37 mmol, 329 μL, 3 eq), sodium2-(4-methylthiazol-2-yl)propanoate (153 mg, 791 μmol, 1 eq) and HATU(361 mg, 949 μmol, 1.20 eq). The mixture was stirred at 15° C. for 16hours. The mixture was concentrated. H₂O (5 mL) was added and themixture was extracted with DCM (20 mL×2). The combined organic layer waswashed with H₂O (20 mL), brine (20 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on silicagel (0%˜50% ethyl acetate in petroleum ether) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-(4-methylthiazol-2-yl)propanamide(210 mg, 87% yield).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)-2-(4-methylthiazol-2-yl)propanamide(200 mg, 653 μmol, 1 eq) in dry dioxane (5 mL) was added POCl₃ (200 mg,1.31 mmol, 121 μL, 2 eq). The mixture was heated at 80° C. for 4 hours.The mixture was cooled to 15° C. and poured into water (5 mL). Themixture was adjusted to pH 8 by saturated aqueous NaHCO₃ and extractedwith DCM (20 mL×2). The combined organics were washed with H₂O (20 mL),brine (20 mL), dried over Na₂SO₄, filtered and concentrated to give6-methyl-3-(1-(4-methylthiazol-2-yl)ethyl)imidazo[1,5-a]pyrazin-8-ol(160 mg).

Step 3: To a solution of6-methyl-3-(1-(4-methylthiazol-2-yl)ethyl)imidazo[1,5-a]pyrazin-8-ol(180 mg, 656 μmol, 1 eq) in DMF (5 mL) was added1-(chloromethyl)-4-methoxy-benzene (123 mg, 787 μmol, 107 μL, 1.20 eq)and Cs₂CO₃ (428 mg, 1.31 mmol, 2 eq). The mixture was heated at 60° C.for 2 h. The mixture was concentrated. DCM (20 mL) and H₂O (10 mL) wasadded. The mixture was extracted with DCM (20 mL). The organic layer waswashed with H₂O (20 mL), dried over Na₂SO₄, filtered and concentrated.The residue was purified by preparative LC-MS to give7-(4-methoxybenzyl)-6-methyl-3-(1-(4-methylthiazol-2-yl)ethyl)imidazo[1,5-a]pyrazin-8(7H)-one(30 mg, 12% yield).

¹H NMR (CDCl₃ 400 MHz): δ 7.95 (s, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.91 (s,1H), 6.82 (d, J=8.4 Hz, 2H), 6.79 (s, 1H), 5.19-5.06 (m, 2H), 4.76 (q,J=7.2 Hz, 1H), 3.76 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H), 1.92 (d, J=7.2Hz, 1H).

LC-MS: t_(R)=2.532 min (method 11), m/z=395.1 [M+H]⁺.

Example 91

3-(7-(4-methoxybenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)-3-methylpyrrolidine-1-sulfonamide

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(200 mg, 1.05 mmol, 1 eq, HCl) and1-((benzyloxy)carbonyl)-3-methylpyrrolidine-3-carboxylic acid (304 mg,1.16 mmol, 1.10 eq) in DCM (10 mL) was added HATU (479 mg, 1.26 mmol,1.20 eq) and DIPEA (407 mg, 3.15 mmol, 550 μL, 3 eq). The mixture wasstirred at 18° C. for 16 hours. The mixture was quenched with H₂O (30mL) and extracted with DCM (25 mL×3). The combined organic layers weredried over Na₂SO₄ and concentrated under vacuum. Benzyl3-(((3-methoxy-5-methylpyrazin-2-yl)methyl)carbamoyl)-3-methylpyrrolidine-1-carboxylate(420 mg, 1.01 mmol, 96% yield) was obtained.

Step 2: To a solution of benzyl3-(((3-methoxy-5-methylpyrazin-2-yl)methyl)carbamoyl)-3-methylpyrrolidine-1-carboxylate(390 mg, 979 μmol, 1 eq) in dioxane (15 mL) was added POCl₃ (300 mg,1.96 mmol, 182 μL, 2 eq). The mixture was stirred at 80° C. for 3 hours.The solution was quenched with H₂O (20 mL) and extracted with DCM (20mL×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under vacuum. Benzyl3-methyl-3-(6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(170 mg, 423 μmol, 43% yield) was obtained.

Step 3: To a solution of benzyl3-methyl-3-(6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(290 mg, 791 μmol, 1 eq) and di-tert-butyl dicarbonate (207 mg, 950μmol, 218 μL, 1.20 eq) in MeOH (200 mL) was added Pd/C (10%, wet) (140mg). The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (30 psi) at 25° C. for 5 hours.The mixture was filtered. The filtered solution was concentrated undervacuum. tert-butyl3-methyl-3-(6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(204 mg, 614 μmol, 78% yield) was obtained.

Step 4: To a solution of tert-butyl3-methyl-3-(6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate(274 mg, 824 μmol, 1 eq) and 1-(chloromethyl)-4-methoxybenzene (155 mg,989 μmol, 135 μL, 1.20 eq) in DMF (15 mL) was added Cs₂CO₃ (537 mg, 1.65mmol, 2 eq). The mixture was stirred at 80° C. for 14 hours. The mixturewas concentrated under vacuum. The mixture was washed with H₂O (15 mL)and extracted with DCM (15 mL×3). The combined organic layers werewashed with H₂O (30 mL×2), dried over Na₂SO₄ and concentrated undervacuum. tert-butyl3-(7-(4-methoxybenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)-3-methylpyrrolidine-1-carboxylate(291 mg, 537 μmol, 65% yield) was obtained.

Step 5: To a solution of tert-butyl3-(7-(4-methoxybenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)-3-methylpyrrolidine-1-carboxylate(288 mg, 636 μmol, 1 eq) in ethyl acetate (4 mL) was added HCl/EtOAc (4M, 4 mL, 25 eq). The mixture was stirred at 18° C. for 4 hours. Themixture was concentrated under vacuum.7-(4-methoxybenzyl)-6-methyl-3-(3-methylpyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(247 mg, crude, HCl) was obtained. The product was directly used for thenext step.

Step 6: To a solution of7-(4-methoxybenzyl)-6-methyl-3-(3-methylpyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(250 mg, 709 μmol, 1 eq) and sulfuric diamide (82 mg, 851 μmol, 51 μL,1.20 eq) in dioxane (20 mL) was added DIPEA (183 mg, 1.42 mmol, 248 μL,2 eq). The mixture was stirred at 100° C. for 24 hours. The mixture wasquenched with H₂O (20 mL) and extracted with DCM (20 mL×3). The combinedorganic layers were dried over Na₂SO₄ and concentrated under vacuum. Theresidue was purified pre-HPLC (base).3-(7-(4-methoxybenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)-3-methylpyrrolidine-1-sulfonamide(14 mg, 32 μmol, 5% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.91 (s, 1H), 7.16 (d, J=8.4 HZ, 2H), 7.85 (s,1H), 7.18 (d, J=8.0 HZ, 2H), 6.88-6.82 (m, 3H), 5.17 (s, 2H), 4.79 (m,1H), 4.30 (d, J=10.4 HZ, 1H), 3.79 (s, 3H), 3.52-3.47 (m, 2H), 3.26-3.20(m, 1H), 2.73-2.64 (m, 1H), 2.23-2.17 (m, 5H), 1.65-1.59 (m, 4H).

LC-MS: t_(R)=2.055 min (method 13), m/z=432.2 [M+H]⁺.

Example 92

6-(cyclopentylmethyl)-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

6-(bromomethyl)-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(250 mg, 0.439 mmol) was dissolved in THF (20 ml), at −78° C.cyclopentylmagnesium bromide (0.9 ml, 1.8 mmol, 2 molar in ether) wasadded and the reaction was allowed to warm to room temperatureovernight. Cyclopentylmagnesium bromide (0.9 ml, 1.8 mmol, 2 molar inether) was added. After 1 hour the reaction was warmed to roomtemperature. After two hours, the reaction mixture was quenched withsat. NH₄Cl, extracted with AcOEt and organics were washed with brine.The combined organics layers were dried with Na₂SO₄, filtered andconcentrated. The mixture was purified via preparative LC-MS and6-(cyclopentylmethyl)-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(26 mg, 0.049 mmol) was isolated in 11% yield, as the TFA salt.

¹H NMR (500 MHz, Chloroform-d) δ 13.26 (bs, 1H), 8.14 (s, 1H), 7.12 (d,J=8.2 Hz, 2H), 6.88 (m, 3H), 5.21 (s, 2H), 4.16 (d, J=11.7 Hz, 2H), 3.80(s, 3H), 3.60 (t, J=11.8 Hz, 2H), 3.46 (t, J=12.4 Hz, 1H), 2.74 (s, 1H),2.57 (d, J=7.0 Hz, 2H), 2.25-2.07 (m, 2H), 1.90 (m, 4H), 1.65 (m, 4H),1.23 (dt, J=13.2, 7.1 Hz, 2H).

LC-MS: t_(R)=0.69 min (method 5), m/z=422.0 [M+H]⁺.

Example 93

7-(4-methoxybenzyl)-6-methyl-3-morpholinoimidazo[1,5-a]pyrazin-8(7H)-one

To a mixture of3-bromo-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (300mg, 0.86 mmol) and morpholine (150 mg, 1.72 mmol) in DMSO (5 mL) wereadded CsF (261 mg, 1.72 mmol) and K₂CO₃ (238 mg, 1.72 mmol). The mixturewas stirred at 100° C. for 24 hours. The mixture was diluted with water(20 mL) and extracted with DCM (10 mL×3). The combine organic layerswere washed with water (10 mL×2); dried over Na₂SO₄ and evaporated undervacuum. The residue was purified by preparative TLC (ethyl acetate) togive7-(4-methoxybenzyl)-6-methyl-3-morpholinoimidazo[1,5-a]pyrazin-8(7H)-one(18 mg, 6% yield).

¹H NMR (CDCl₃, 400 MHz): δ 7.76 (s, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.85(d, J=8.8 Hz, 2H), 6.63 (s, 1H), 5.15 (s, 2H), 3.89 (t, J=4.8 Hz, 4H),3.79 (s, 3H), 3.21 (t, J=4.8 Hz, 4H), 2.18 (s, 3H).

LC-MS: t_(R)=2.03 min (method 13), m/z=355.1 [M+H].

Example 94

7-(4-methoxybenzyl)-6-methyl-3-((tetrahydrofuran-3-yl)amino)imidazo[1,5-a]pyrazin-8(7H)-one

3-bromo-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (60mg, 0.172 mmol) and tetrahydrofuran-3-amine (0.04 ml, 0.465 mmol) weremixed in NMP (2 mL) and DIPEA (0.23 ml, 1.317 mmol).

The reaction was heated for 4 hours at 250° C. in the microwave oven.

The reaction was purified on silica gel, via preparative LC-MS, andpreparative TLC (10% EtOH in ethyl acetate) to give7-(4-methoxybenzyl)-6-methyl-3-((tetrahydrofuran-3-yl)amino)imidazo[1,5-a]pyrazin-8(7H)-one(2 mg, 0.005 mmol) in 3% yield.

¹H NMR (600 MHz, Dimehtylsulfoxide-d₆) δ 8.50 (m, NH), 7.68 (s, 1H),7.31 (s, 1H) 7.22 (d, J=7.1 Hz, 2H), 6.88 (d, J=7.1 Hz, 2H), 4.87 (m,1H), 4.35 (d, J=14 Hz, 2H), 4.11 (m, 1H), 4.02 (m, 1H), 3.92 (m, 1H),3.86 (m, 1H), 3.71 (s, 3H), 2.60 (m, 1H), 2.5 (m, 1H) 2.31 (s, 3H).

LC-MS: t_(R)=0.54 min (method 19), m/z=355.2 [M+H]⁺.

Example 95

(R)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one

3-bromo-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (80mg, 0.23 mmol) and (R)-3-methylmorpholine (34.7 mg, 0.039 ml, 0.343mmol) were mixed in NMP (2.0 mL) and DIPEA (0.2 ml, 1.1 mmol) was added.

The reaction was heated for 6.5 hours at 250° C. in the microwave oven.

The reaction was purified directly by preparative LC-MS to give(R)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one(10 mg, 0.024 mmol) in 10% yield.

¹H NMR (500 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.18 (d, J=7.1 Hz, 2H),6.90 (d, J=7.1 Hz, 2H), 6.79 (s, 1H), 5.23 (d, J=14.0 Hz, 1H), 5.13 (d,J=15.7 Hz, 1H), 3.94 (m, 1H), 3.85 (m, 1H), 3.81 (s, 3H), 3.60 (m, 1H),3.48 (dd, J=11.7, 7.9 Hz, 1H), 3.32 (t, J=10.3 Hz, 1H), 3.22 (d, J=12.2Hz, 1H), 2.28 (d, J=1.6 Hz, 3H), 1.29 (td, J=7.1, 1.6 Hz, 1H), 1.00 (dd,J=6.4, 1.5 Hz, 3H).

LC-MS: t_(R)=0.65 min (method 7), m/z=369.1 [M+H]⁺.

Example 96

(S)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one

3-bromo-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (80mg, 0.230 mmol) and (S)-3-methylmorpholine (0.039 ml, 0.343 mmol) weremixed in NMP (2 mL) and DIPEA (148 mg, 0.2 ml, 1.1 mmol).

The reaction was heated for 6.5 hours at 250° C., in the microwave oven.The reaction was purified directly by preparative LC-MS to give(S)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one(10 mg, 0.028 mmol) in 12% yield.

¹H NMR (500 MHz, Chloroform-d) b 8.00 (s, 1H), 7.18 (d, J=7.1 Hz, 2H),6.90 (d, J=7.1 Hz, 2H), 6.79 (s, 1H), 5.23 (d, J=14.0 Hz, 1H), 5.13 (d,J=15.7 Hz, 1H), 3.94 (m, 1H), 3.85 (m, 1H), 3.81 (s, 3H), 3.60 (m, 1H),3.48 (dd, J=11.7, 7.9 Hz, 1H), 3.32 (t, J=10.3 Hz, 1H), 3.22 (d, J=12.2Hz, 1H), 2.28 (d, J=1.6 Hz, 3H), 1.29 (td, J=7.1, 1.6 Hz, 1H), 1.00 (dd,J=6.4, 1.5 Hz, 3H).

LC-MS: t_(R)=0.65 min (method 7), m/z=369.1 [M+H]⁺.

Example 97

7-(4-methoxybenzyl)-6-methyl-3-(1,4-oxazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one

3-bromo-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (149mg, 0.428 mmol) and 1,4-oxazepane hydrochloride (100 mg, 0.727 mmol)were mixed in NMP (2.2 mL) and DIPEA (296 mg, 0.4 mL, 2.29 mmol). Thereaction was heated for 3 hours at 250° C.

The reaction was purified directly via preparative LC-MS to afford7-(4-methoxybenzyl)-6-methyl-3-(1,4-oxazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one(27 mg, 0.073 mmol) in 17% yield.

¹H NMR (500 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.14 (m, 2H), 6.87 (m,2H), 6.64 (s, 1H), 5.13 (s, 2H), 3.93 (m, 2H), 3.88 (m, 2H), 3.80 (d,J=1.7 Hz, 3H), 3.73 (m, 4H), 2.22 (s, 3H), 2.09 (m, 2H).

LC-MS: t_(R)=0.56 min (method 7), m/z=369.1 [M+H]⁺.

Example 98

3-(2,2-dimethylmorpholino)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one

To a mixture of3-bromo-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (500mg, 1.44 mmol) and 2,2-dimethylmorpholine (331 mg, 2.88 mmol) in DMSO (5mL) were added CsF (328 mg, 2.88 mmol) and K₂CO₃ (299 mg, 2.88 mmol).The mixture was stirred at 100° C. for 24 hours. The mixture was dilutedwith water (20 mL) and extracted with DCM (10 mL×3). The combinedorganic layer was washed with water (10 mL×2); dried over Na₂SO₄ andevaporated under vacuum. The residue was purified by preparative TLC(ethyl acetate) to give3-(2,2-dimethylmorpholino)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(15 mg, 3% yield).

¹H NMR (CDCl₃, 400 MHz): δ 7.75 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 6.85(d, J=8.8 Hz, 2H), 6.60 (s, 1H), 5.15 (s, 2H), 3.93 (t, J=4.8 Hz, 2H),3.79 (s, 3H), 3.16 (t, J=4.8 Hz, 2H), 2.98 (s, 2H), 2.18 (s, 3H), 1.37(s, 6H).

LC-MS: t_(R)=2.26 min (method 13), m/z=383.1 [M+H].

Example 99

7-(3-fluorobenzyl)-3-(hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 and 2

Step 1: To a solution of 3-bromo-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(3 g, 13.16 mmol) and 1-(bromomethyl)-3-fluorobenzene (2.99 g, 15.79mmol) in DMF (50 mL) was added K₂CO₃ (3.64 g, 26.3 mmol). The mixturewas stirred at 60° C. for 12 hours. The mixture was diluted with water(100 mL) and extracted with EtOAc (50 mL×3). The combined organic layerwas washed with water (50 mL×2); dried over Na₂SO₄ and evaporated undervacuum. The residue was washed with EtOAc (10 mL) and filtrated. Thefilter cake was dried under vacuum to give3-bromo-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (2 g,45% yield).

Step 2: To a mixture of3-bromo-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one (1.2g, 3.57 mmol) and hexahydro-2H-furo[3,2-b]pyrrole (0.5 oxalc acid salt)(678 mg, 4.28 mmol) in DMSO (20 mL) were added CsF (542 mg, 3.57 mmol)and K₂CO₃ (1.23 g, 8.92 mmol). The mixture was stirred at 120° C. for 72hours. The mixture was diluted with water (100 mL) and extracted withDCM (50 mL×3). The combined organic layer was washed with water (50mL×2); dried over Na₂SO₄ and evaporated under vacuum. The residue waspurified by prep-HPLC to give compound 3 (200 mg, 15% yield).

Step 3:7-(3-fluorobenzyl)-3-(hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one(200 mg, 0.54 mmol) was purified by SFC to give stereoisomer 1 (48 mg).

¹H NMR (CDCl₃, 400 MHz): δ7.74 (s, 1H), 7.33-7.29 (m, 1H), 7.01-6.89 (m,3H), 6.73 (s, 1H), 5.19 (s, 2H), 4.72-4.66 (m, 2H), 3.92-3.86 (m, 2H),3.75-3.73 (m, 1H), 3.50-3.47 (m, 1H), 2.16-2.09 (m, 6H), 1.91-1.86 (m,1H).

LC-MS: t_(R)=1.90 min (method 12), m/z=369.1 [M+H]⁺. SFC-MS: t_(R)=4.44min, ee %>99%. [α]_(D) ²⁰+133.00 (c=0.10, DCM).

stereoisomer 2 (32 mg).

¹H NMR (CDCl₃, 400 MHz): δ 7.74 (s, 1H), 7.32-7.28 (m, 1H), 7.01-6.89(m, 3H), 6.73 (s, 1H), 5.19 (s, 2H), 4.74-4.67 (m, 2H), 3.92-3.87 (m,2H), 3.75-3.72 (m, 1H), 3.50-3.47 (m, 1H), 2.16-2.09 (m, 6H), 1.91-1.86(m, 1H).

LC-MS: t_(R)=1.89 min (method 12), m/z=369.1 [M+H]⁺. SFC-MS: t_(R)=5.71min, ee %>99%. [α]_(D) ²⁰−82.00 (c=0.10, DCM).

Example 100

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 1 and 2

Step 1: To a solution of (3-methoxy-5-methylpyrazin-2-yl)methanamine(150 mg, 979.2 μmol), tetrahydro-2H-pyran-3-carboxylic acid (127.4 mg,979.2 μmol) in DCM (10 mL) was added HATU (670.2 mg, 1.8 mmol) andtriethylamine (198.2 mg, 1.9 mmol). The mixture was stirred at 25° C.for 16 hours. The mixture was diluted with water (15 mL), extracted withDCM (3×30 mL). The combined organic layer was washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby preparative TLC (EA/MeOH=20/1) to giveN-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-3-carboxamide(130 mg, 50% yield).

Step 2: To a solution ofN-((3-methoxy-5-methylpyrazin-2-yl)methyl)tetrahydro-2H-pyran-3-carboxamide(130 mg, 490 μmol) in dioxane (3 mL) was added POCl₃ (1.28 g, 490 μmol).The mixture was stirred at 80° C. for 3 h. The mixture was cooled downto 25° C. and concentrated. The residue was neutralized by saturatedaq.NaHCO₃, extracted with ethyl acetate (2×20 mL). The combined organiclayer was washed with brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give crude8-methoxy-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazine(120 mg, 99% yield). The crude was used directly for the next step.

Step 3: To a solution of8-methoxy-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazine(120 mg, 485.3 μmol) in dioxane (3 mL) was added HCl (2 M, 3 mL). Themixture was stirred at 80° C. for 3 h. The mixture was cooled down to25° C. and concentrated, neutralized with saturated aq.NaHCO₃, extractedwith DCM (3×30 mL). The combined organic layer was washed with brine (20mL), dried over Na₂SO₄, filtered and concentrated to give crude6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(110 mg, 97% yield). The crude product was used directly for the nextstep.

Step 4: To a solution of6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(100.0 mg, 428.7 μmol) and 1-(bromomethyl)-3-fluorobenzene (121.6 mg,643.0 μmol) in DMF (5 mL) was added K₂CO₃ (118.5 mg, 857.4 μmol). Themixture was stirred at 80° C. for 2 h. The mixture was cooled down to25° C. and diluted with water (20 mL), extracted with ethyl acetate(3×30 mL). The combined organic layer was washed with brine (30 mL),dried over Na₂SO₄, filtered and concentrated. The residue was purifiedby preparative TLC (PE/EA=1/1) to give7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(80 mg, 54% yield).

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one(80 mg, 234.3 μmol) was purified by SFC.

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereisomer 1 (26 mg, 33% yield) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.33-7.27 (m, 1H), 7.00-6.89 (m,3H), 6.81 (s, 1H), 5.23 (s, 2H), 4.11-4.03 (m, 2H), 3.69 (t, J=11.2 Hz,1H), 3.57-3.53 (m, 1H), 3.17-3.14 (m, 1H), 2.18-2.11 (m, 5H), 1.85-1.79(m, 2H).

LC-MS: t_(R)=2.06 min (method 3), m/z=342.1 [M+H]⁺. SFC: t_(R)=5.286min, ee %>99%. α_(D) ²⁰=−3.0 (c=0.10, CHCl₃).

7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one,stereoisomer 2 (28 mg, yield: 35%) was obtained.

¹H NMR (CDCl₃ 400 MHz): δ 7.92 (s, 1H), 7.31-7.27 (m, 1H), 7.00-6.89 (m,3H), 6.81 (s, 1H), 5.22 (s, 2H), 4.11-4.03 (m, 2H), 3.68 (t, J=11.2 Hz,1H), 3.57-3.53 (m, 1H), 3.17-3.14 (m, 1H), 2.18-2.11 (m, 5H), 1.84-1.78(m, 2H).

LC-MS: t_(R)=2.06 min (method 3), m/z=342.2 [M+H]⁺. SFC: t_(R)=6.404min, ee %>99%. α_(D) ²⁰=+3.0 (C=0.10, CHCl₃).

In Vitro Testing

PDE1 Inhibition Assay

PDE1A, PDE1B and PDE1C assays were performed as follows: the assays wasperformed in 60 μL samples containing a fixed amount of the PDE1 enzyme(sufficient to convert 20-25% of the cyclic nucleotide substrate), abuffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20), 0.1 mg/ml BSA,15 nM tritium labelled cAMP and varying amounts of inhibitors. Reactionswere initiated by addition of the cyclic nucleotide substrate, andreactions were allowed to proceed for 1 h at room temperature beforebeing terminated through mixing with 20 μL (0.2 mg) yttrium silicate SPAbeads (PerkinElmer). The beads were allowed to settle for 1 h in thedark before the plates were counted in a Wallac 1450 Microbeta counter.The measured signals were converted to activity relative to anuninhibited control (100%) and IC₅₀ values were calculated using XlFit(model 205, IDBS).

PDE9 Inhibition Assay

A PDE9 assay may for example, be performed as follows: The assay isperformed in 60 μL samples containing a fixed amount of the relevant PDEenzyme (sufficient to convert 20-25% of the cyclic nucleotidesubstrate), a buffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20),0.1 mg/mi BSA, 225 pCi of ³H-labelled cyclic nucleotide substrate,tritium labeled cAMP to a final concentration of 5 nM and varyingamounts of inhibitors. Reactions are initiated by addition of the cyclicnucleotide substrate, and reactions are allowed to proceed for one hr atroom temperature before being terminated through mixing with 15 μL 8mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed tosettle for one hr in the dark before the plates are counted in a Wallac1450 Microbeta counter. The measured signal can be converted to activityrelative to an uninhibited control (100%) and IC₅₀ values can becalculated using the Xlfit extension to EXCEL.

In the context of the present invention the assay was performed in 60 μLassay buffer (50 mM HEPES pH 7.6; 10 mM MgCl₂; 0.02% Tween20) containingenough PDE9 to convert 20-25% of 10 nM ³H-cAMP and varying amounts ofinhibitors. Following a 1 hr incubation the reactions were terminated byaddition of 15 μL 8 mg/mL yttrium silicate SPA beads (Amersham). Thebeads were allowed to settle for one hr in the dark before the plateswere counted in a Wallac 1450 Microbeta counter.

The invention claimed is:
 1. A combination of: 1) a compound of Formula(I):

or a pharmaceutically acceptable addition salt or tautomer thereof,wherein: R₁ is: (a) benzyl, optionally substituted on the phenyl ringwith a substituent selected from the group consisting of halogen andC₁-C₃ alkyl; (b) linear or branched C₁-C₈ alkyl, optionally substitutedwith one or more substituents independently selected from the groupconsisting of fluoro, cyano, methyl, hydroxy, and methoxy; (c) linear orbranched C₁-C₃ alkyl, substituted with a substituent selected from thegroup consisting of phenyl and a 5-membered heteroaryl, wherein the5-membered heteroaryl is optionally substituted with one or moreindependently selected C₁-C₃ alkyl; (d) a saturated, monocyclic C₃-C₈cycloalkyl, optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, cyano,methyl, hydroxy, and methoxy; (e) indanyl, optionally substituted with asubstituent selected from the group consisting of halogen and C₁-C₃alkyl; (f) a saturated, monocyclic ring containing 4, 5, or 6 carbonatoms and 1 or 2 nitrogen atoms, optionally substituted with one or moresubstituents independently selected from the group consisting of fluoro,methyl, and sulfonamido; (g) a lactam containing 4, 5, or 6 carbonatoms, optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro and methyl;(h) oxetanyl, optionally substituted with one or more substituentsindependently selected from the group consisting of fluoro, cyano,methyl, hydroxy, and methoxy; (i) tetrahydrofuranyl, optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, cyano, methyl, hydroxy, and methoxy; (j)3-aminotetrahydrofuranyl, optionally substituted with one or moreindependently selected C₁-C₃ alkyl; (k) tetrahydropyranyl, optionallysubstituted with one or more substituents independently selected fromthe group consisting of fluoro, cyano, methyl, hydroxy, and methoxy; (l)morpholinyl, optionally substituted with one or more independentlyselected C₁-C₃ alkyl; (m) 1,4-oxazepanyl, optionally substituted withone or more independently selected C₁-C₃ alkyl; (n) a 5-memberedheteroaryl, optionally substituted with a substituent selected from thegroup consisting of halogen and C₁-C₃ alkyl; (o) indolinyl, optionallysubstituted with a substituent selected from the group consisting ofhalogen and C₁-C₃ alkyl; (p) a bicyclic ether, optionally substitutedwith one or more substituents independently selected from the groupconsisting of fluoro and methyl; or (q)hexahydro-2H-furo[3,2-b]pyrrolyl, optionally substituted with one ormore independently selected C₁-C₃ alkyl; R₂ is: (a) hydrogen; (b) linearor branched C₁-C₈ alkyl; (c) a saturated, monocyclic C₃-C₈ cycloalkyl;(d) oxetanyl; (e) tetrahydrofuranyl; (f) tetrahydropyranyl; (g)benzo[d][1,3]dioxolyl; (h) phenyl, optionally substituted with one ormore substituents independently selected from the group consisting ofhalogen, cyano, C₁-C₃ alkyl, amino, NHC(O)CH₃, hydroxy, C₁-C₃ alkoxy,C₁-C₃ fluoroalkoxy, OCH₂—(C₃-C₅ cycloalkyl), and C₃-C₅ cycloalkoxy; (i)a 5-membered heteroaryl, optionally substituted with one or moreindependently selected C₁-C₃ alkyl; or (j) pyridyl, substituted with oneor more substituents independently selected from the group consisting ofhalogen, cyano, C₁-C₃ alkyl, amino, NHC(O)CH₃, hydroxy, C₁-C₃ alkoxy,C₁-C₃ fluoroalkoxy, OCH₂—(C₃-C₅ cycloalkyl), and C₃-C₅ cycloalkoxy; R₃is: (a) hydrogen; (b) halogen; (c) C₁-C₂ alkyl, optionally substitutedwith one, two, or three fluoro; (d) C₃-C₅ alkyl; (e) C₃-C₅ cycloalkyl;or (f) phenyl, optionally substituted with one or more independentlyselected C₁-C₃ alkyl; R₄ is hydrogen; n is 0 or 1; and q is 0 or 1; withthe proviso that R₂ and R₃ are not simultaneously hydrogen; and 2) asecond compound selected from the group consisting of amisulpride,aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine,chlorpromazine, clozapine, flupenthixol, fluphenazine, haloperidole,iloperidone, levomepromazine, lurasidone, olanzapine, paliperidone,perphenazine, quetiapine, risperidone, sulpiride, ziprasidone, andzuclopenthixol.
 2. The combination according to claim 1, wherein: R₁ is:(a) linear or branched C₁-C₈ alkyl; (b) a saturated, monocyclic C₃-C₈cycloalkyl; (c) oxetanyl; (d) tetrahydrofuranyl; or (e)tetrahydropyranyl; R₂ is: (a) linear or branched C₁-C₈ alkyl; (b) asaturated, monocyclic C₃-C₈ cycloalkyl; or (c) phenyl, optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₃ alkyl, and methoxy; and R₃ is:(a) hydrogen; (b) halogen; or (c) C₁-C₃ alkyl.
 3. The combinationaccording to claim 1, wherein the compound of Formula (I) is selectedfrom the group consisting of:7-(3-Fluorobenzyl)-3-propylimidazo[1,5-a]pyrazin-8(7H)-one;6-Benzyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Benzyl-7-(cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclohexylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-Cyclopropyl-7-(3-fluorobenzyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclopentylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclohexylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclopentylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cycloheptylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cycloheptylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Bromo-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-Benzyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(2-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(2-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Methyl-7-(2-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Methyl-7-(4-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-Methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Methyl-7-(3-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;4-(7-(3-fluorobenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile;7-(3-fluorobenzyl)-3-(4-methoxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-(4-fluorotetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(2,2-difluorocyclopropyl)-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1R,2S)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1R,2R)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1S,2S)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1S,2R)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2S,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2S,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2R,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2R,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1R,2S)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1R,2R)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1S,2S)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1S,2R)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-cyclopropoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-(difluoromethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(4-(trifluoromethoxy)benzyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-(cyclopropylmethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-benzyl-6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-ethyl-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile;4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile;N-(4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)phenyl)acetamide;7-(4-chloro-3-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(2-ethylbenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(benzo[d][1,3]dioxol-5-ylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-chloro-4-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-aminobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-hydroxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-ethyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2S,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2S,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2R,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2R,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one;7-((6-methoxypyridin-3-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-ethyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-propyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-isopropyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-isopentyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(cyclopentylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;2-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile;7-(cycloheptylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((1R,2R,4S)-2-methyl-7-oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(1,4-dimethylpiperidin-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(3-methyl-5-oxopyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(1-methoxy-2-methylpropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;3-isopropyl-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-((2-methylthiazol-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiophen-3-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiazol-4-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-((3,5-dimethylisoxazol-4-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-((5-methylisoxazol-3-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-((3-methylisoxazol-5-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(cyclohexylmethyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one;3-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;3-(2-fluoropropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(7-oxoazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(5-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(1-(4-methylthiazol-2-yl)ethyl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(7-(4-methoxybenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)-3-methylpyrrolidine-1-sulfonamide;6-(cyclopentylmethyl)-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(morpholino)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((tetrahydrofuran-3-yl)amino)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(1,4-oxazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(2,2-dimethylmorpholino)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((3aS,6aS)-hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((3aR,6aR)-hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;and(S)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;and pharmaceutically acceptable salts thereof.
 4. A pharmaceuticalcomposition comprising the combination according to claim 1 and one ormore pharmaceutically acceptable carriers, diluents, or excipients. 5.The pharmaceutical composition according to claim 4, wherein: R₁ is: (a)linear or branched C₁-C₈ alkyl; (b) a saturated, monocyclic C₃-C₈cycloalkyl; (c) oxetanyl; (d) tetrahydrofuranyl; or (e)tetrahydropyranyl; R₂ is: (a) linear or branched C₁-C₈ alkyl; (b) asaturated, monocyclic C₃-C₈ cycloalkyl; or (c) phenyl, optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, C₁-C₃ alkyl, and methoxy; and R₃ is:(a) hydrogen; (b) halogen; or (C) C₁-C₃ alkyl.
 6. The pharmaceuticalcomposition according to claim 4, wherein the compound of Formula (I) isselected from the group consisting of:7-(3-Fluorobenzyl)-3-propylimidazo[1,5-a]pyrazin-8(7H)-one;6-Benzyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Benzyl-7-(cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclohexylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-Cyclopropyl-7-(3-fluorobenzyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclopentylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclohexylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclopentylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cyclohexylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cycloheptylmethyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(Cycloheptylmethyl)-3-cyclopropylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Bromo-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-Benzyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(2-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(2-Chlorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-Methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Methyl-7-(2-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Methyl-7-(4-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-Methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-Fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-Methyl-7-(3-methylbenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-(4-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;4-(7-(3-fluorobenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)tetrahydro-2H-pyran-4-carbonitrile;7-(3-fluorobenzyl)-3-(4-methoxytetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-(4-fluorotetrahydro-2H-pyran-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(3-fluorobenzyl)-6-methyl-3-(3-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-(1-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(2,2-difluorocyclopropyl)-7-(3-fluorobenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1R,2S)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1R,2R)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1S,2S)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((1S,2R)-2-methylcyclopropyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2S,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2S,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2R,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-6-methyl-3-((2R,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1R,2S)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1R,2R)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1S,2S)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((1S,2R)-2-fluorocyclopropyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-cyclopropoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-(difluoromethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(4-(trifluoromethoxy)benzyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-(cyclopropylmethoxy)benzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-benzyl-6-ethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-ethyl-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile;4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile;N-(4-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)phenyl)acetamide;7-(4-chloro-3-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(2-ethylbenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(benzo[d][1,3]dioxol-5-ylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(3-chloro-4-methoxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-aminobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-hydroxybenzyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-ethyl-7-(3-fluorobenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2S,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2S,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2R,3R)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((2R,3S)-2-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one;7-((6-methoxypyridin-3-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6,7-dimethyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-ethyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-propyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-isopropyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-isopentyl-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(cyclopentylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;2-((6-methyl-8-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-7(8H)-yl)methyl)benzonitrile;7-(cycloheptylmethyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((1R,2R,4S)-2-methyl-7-oxabicyclo[2.2.1]heptan-2-yl)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(4-methoxybenzyl)-6-methyl-3-(1-phenylethyl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(1,4-dimethylpiperidin-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;3-(6-chloro-2,3-dihydro-1H-inden-1-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(3-methyl-5-oxopyrrolidin-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(1-methoxy-2-methylpropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;3-isopropyl-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-((2-methylthiazol-4-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiophen-3-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-3-(tetrahydro-2H-pyran-4-yl)-7-(thiazol-4-ylmethyl)imidazo[1,5-a]pyrazin-8(7H)-one;7-((3,5-dimethylisoxazol-4-yl)methyl)-6-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-((5-methylisoxazol-3-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;6-methyl-7-((3-methylisoxazol-5-yl)methyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(cyclohexylmethyl)-6-methyl-3-propylimidazo[1,5-a]pyrazin-8(7H)-one;3-(2-hydroxypropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;3-(2-fluoropropan-2-yl)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(7-oxoazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(5-methyltetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(1-(4-methylthiazol-2-yl)ethyl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(7-(4-methoxybenzyl)-6-methyl-8-oxo-7,8-dihydroimidazo[1,5-a]pyrazin-3-yl)-3-methylpyrrolidine-1-sulfonamide;6-(cyclopentylmethyl)-7-(4-methoxybenzyl)-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(morpholino)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-((tetrahydrofuran-3-yl)amino)imidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one;(S)-7-(4-methoxybenzyl)-6-methyl-3-(3-methylmorpholino)imidazo[1,5-a]pyrazin-8(7H)-one;7-(4-methoxybenzyl)-6-methyl-3-(1,4-oxazepan-4-yl)imidazo[1,5-a]pyrazin-8(7H)-one;3-(2,2-dimethylmorpholino)-7-(4-methoxybenzyl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((3aS,6aS)-hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;7-(3-fluorobenzyl)-3-((3aR,6aR)-hexahydro-4H-furo[3,2-b]pyrrol-4-yl)-6-methylimidazo[1,5-a]pyrazin-8(7H)-one;(R)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;and(S)-7-(3-fluorobenzyl)-6-methyl-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-8(7H)-one;and pharmaceutically acceptable salts thereof.
 7. A method forinhibiting phosphodiesterase 1 activity in a patient, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the combination according to claim
 1. 8. The method accordingto claim 7, wherein the patient has a disorder selected from the groupconsisting of a psychiatric disorder and a cognitive disorder.
 9. Themethod according to claim 8, wherein the psychiatric disorder orcognitive disorder is selected from the group consisting of attentiondeficit hyperactivity disorder, depression, anxiety, narcolepsy,schizophrenia, and cognitive impairment.
 10. The method according toclaim 9, wherein the cognitive impairment is cognitive impairmentassociated with schizophrenia.
 11. A method for inhibitingphosphodiesterase 1 activity in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of thepharmaceutical composition according to claim
 4. 12. The methodaccording to claim 11, wherein the patient has a disorder selected fromthe group consisting of a psychiatric disorder and a cognitive disorder.13. The method according to claim 12, wherein the psychiatric disorderor cognitive disorder is selected from the group consisting of attentiondeficit hyperactivity disorder, depression, anxiety, narcolepsy,schizophrenia, and cognitive impairment.
 14. The method according toclaim 13, wherein the cognitive impairment is cognitive impairmentassociated with schizophrenia.
 15. A method for inhibitingphosphodiesterase 1 activity in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of thepharmaceutical composition according to claim
 5. 16. The methodaccording to claim 15, wherein the patient has a disorder selected fromthe group consisting of a psychiatric disorder and a cognitive disorder.17. The method according to claim 16, wherein the psychiatric disorderor cognitive disorder is selected from the group consisting of attentiondeficit hyperactivity disorder, depression, anxiety, narcolepsy,schizophrenia, and cognitive impairment.
 18. The method according toclaim 17, wherein the cognitive impairment is cognitive impairmentassociated with schizophrenia.
 19. A method for inhibitingphosphodiesterase 1 activity in a patient, comprising administering to apatient in need thereof a therapeutically effective amount of thepharmaceutical composition according to claim
 6. 20. The methodaccording to claim 4, wherein the patient has a disorder selected fromthe group consisting of a psychiatric disorder and a cognitive disorder.21. The method according to claim 20, wherein the psychiatric disorderor cognitive disorder is selected from the group consisting of attentiondeficit hyperactivity disorder, depression, anxiety, narcolepsy,schizophrenia, and cognitive impairment.
 22. The method according toclaim 21, wherein the cognitive impairment is cognitive impairmentassociated with schizophrenia.